Compositions and methods for treating disorders ameliorated by muscarinic receptor activation

ABSTRACT

Provided herein is an oral pharmaceutical composition, comprising a plurality of xanomeline beads having a core comprising xanomeline or a salt thereof; and a plurality of trospium beads having a core comprising a salt of trospium.

This application claims the benefit of the filing date as a continuationof U.S. patent application Ser. No. 17/143,904, filed on Jan. 7, 2021,which is a continuation of United States patent application No.16,585,532, filed on Sep. 27, 2019 (now U.S. Pat. No. 10,933,020), andclaims the benefit of priority of U.S. Provisional Patent ApplicationSer. No. 62/738,333 filed Sep. 28, 2018, the disclosures of which areeach incorporated by reference in their entireties for all purposes.

The present disclosure relates to compositions and their application aspharmaceuticals for treating disorders ameliorated by activatingmuscarinic receptors in a human or animal subject.

Schizophrenia affects about 0.5 to 1% of the population. The disease ischaracterized by a set of symptoms divided into positive symptoms (e.g.,hallucinations, delusional thoughts, etc.), negative symptoms (e.g.,social isolation, anhedonia, etc.), and cognitive symptoms (e.g.,inability to process information, poor working memory, etc.). Patientswho suffer from schizophrenia experience a major decline in quality oflife and are at increased risk for mortality due to many factors, suchas an increased suicide rate. The cost of schizophrenia to society ishigh, as sufferers of schizophrenia are much more likely to beincarcerated, homeless, or unemployed.

Existing treatments for schizophrenia rely upon dopamine and serotoninreceptors, as was the case with the first antipsychotic, chlorpromazine,discovered in 1952. For more than 60 years, the same fundamentalpharmacology has been the standard of care in schizophrenia. Currentantipsychotics are only efficacious toward positive symptoms, leavingnegative and cognitive symptoms untreated. Alzheimer's disease isanother therapeutic area in which it has proven extremely difficult todevelop new therapies, with a success rate of only 0.4% for moleculesthat enter clinical development and receive marketing approval. Newtreatments are desperately needed by patients in these areas, butdevelopment has been extremely difficult despite substantial effortsfrom scientists and drug developers around the world.

Activating the muscarinic system through muscarinic agonists may treatseveral diseases, such as schizophrenia, Alzheimer's disease,Parkinson's disease, depression, movement disorders, drug addiction,pain, and neurodegeneration, such as tauopathies or synucleinopathies.Muscarinic cholinergic receptors are G-protein coupled receptors withfive different receptor subtypes (M1-M5), each of which is found in theCNS with different tissue distributions. M1 and M4 subtypes have been ofinterest as therapeutic targets for various diseases. For instance, themood stabilizers lithium and valproic acid, used for treating bipolardepression, may exert their effects via the muscarinic system,particularly through the M4 subtype receptor. Genetic evidence directlylinks the muscarinic system and alcohol addiction.

In a double-blind placebo-controlled trial of schizophrenic patientsusing xanomeline, a muscarinic cholinergic receptor agonist withpreferential activity at the M1 and M4 subtype receptors, schizophreniawas alleviated. However, because xanomeline also bound to muscarinicreceptors outside the brain, many serious side effects resulted,including GI side effects, cardiac side effects, and hypersalivation.Dose-limited adverse events were problematic and led to very highdiscontinuation rates (including a 56% dropout rate in a 26-week studyof Alzheimer's disease) and eventually to discontinuation of xanomelinedevelopment. Despite the early promise, xanomeline development haltedfor more than 15 years. Many companies attempted and failed to developmuscarinic receptor agonists for CNS disorders, which avoided theseunacceptable side effects, but no such agonist has reached the market.Past development efforts focused on medicinal chemistry to developmolecules that would be more tolerable, typically by selecting for theM1 and M4 subtypes over the M2 and M3 muscarinic receptor subtypes.However, M1 and/or M4 activation outside the brain may still causemuscarinic related intolerance. Very little progress has been made tomitigate adverse effects due to the activation of peripheral muscarinicreceptors.

There remains a need in the art for a pharmaceutical composition withincreased tolerability for xanomeline, especially to treat cognitive andpsychotic disorders. The following embodiments and aspects thereof aredescribed and illustrated with compositions and methods, which are meantto be exemplary and illustrative, not limiting in scope. In variousembodiments, one or more of the above-described problems have beenreduced or eliminated, while other embodiments are directed to otherimprovements.

Provided herein is an oral pharmaceutical composition, comprising aplurality of xanomeline beads comprising xanomeline or a salt thereof;and a plurality of trospium beads comprising a salt of trospium.

In certain embodiments, the size of the xanomeline beads is between0.425 mm and 1.18 mm. In certain embodiments, the size of the xanomelinebeads is between 0.6 mm and 0.85 mm. In certain embodiments, the size ofthe trospium beads is between 0.425 mm and 1.18 mm. In certainembodiments, the size of the trospium beads is between 0.6 mm and 0.85mm.

In certain embodiments, the xanomeline beads contain about 2.5 times asmuch xanomeline as the trospium beads contain trospium chloride.

In certain embodiments, the plurality of xanomeline and the plurality oftrospium beads have a dissolution rate of more than about 95% withinabout the first 45 minutes following contact with an aqueous solution.In certain embodiments, the dissolution rate of more than about 95%occurs within about the first 20 minutes following contact with anaqueous solution.

In certain embodiments, when administered to a patient for at least 7days at 20 mg trospium twice daily, the oral pharmaceutical compositionprovides a mean C_(max) of trospium at 7850±3360 pg/mL. In certainembodiments, when administered to a patient for at least 7 days at 20 mgtrospium twice daily, oral pharmaceutical composition provides a meanAUC₀₋₁₂ of 41900±15500 hr·pg/mL.

In certain embodiments, the xanomeline salt is xanomeline tartrate. Incertain embodiments, the xanomeline beads comprise between 30 wt. % and80 wt. % xanomeline tartrate, such as 66 wt. % xanomeline tartrate. Incertain embodiments, the xanomeline beads comprise between 15 wt. % and65 wt. % microcrystalline cellulose, such as 33.5 wt. % microcrystallinecellulose. In certain embodiments, the xanomeline beads comprise between0 wt. % and 2 wt. % talc, such as 0.5 wt. % talc. In certainembodiments, the xanomeline beads comprise between 30 wt. % and 80 wt. %xanomeline tartrate, between 15 wt. % and 65 wt. % microcrystallinecellulose, and between 0 wt. % and 2 wt. % talc. In certain embodiments,the xanomeline beads comprise 66 wt. % xanomeline tartrate, 33.5 wt. %microcrystalline cellulose, and 0.5 wt. % talc.

In certain embodiments, the trospium salt is trospium chloride. Incertain embodiments, the trospium beads comprise between 8 wt. % and 35wt. % trospium chloride, such as 17.7 wt. % trospium chloride. Incertain embodiments, the trospium beads comprise between 25 wt. % and 80wt. % microcrystalline cellulose, such as 46.8 wt. % microcrystallinecellulose. In certain embodiments, the trospium beads comprise between15 wt. % and 70 wt. % lactose monohydrate, such as 35 wt. % lactosemonohydrate. In certain embodiments, the trospium beads comprise between0 wt. % and 2 wt. % talc, such as 0.5 wt. % talc. In certainembodiments, the trospium beads comprise between 8 wt. % and 35 wt. %trospium chloride, between 25 wt. % and 80 wt. % microcrystallinecellulose, between 15 wt. % and 70 wt. % lactose monohydrate, andbetween 0 wt. % and 2 wt. % talc. In certain embodiments, the trospiumbeads comprise 17.7 wt. % trospium chloride, 46.8 wt. % microcrystallinecellulose, 35 wt. % lactose monohydrate, and 0.5 wt. % talc.

In certain embodiments, the oral pharmaceutical composition furthercomprises a capsule containing the plurality of xanomeline beads and theplurality of trospium beads. In certain embodiments, the capsule has adosage strength of 50 mg xanomeline free base and 20 mg trospiumchloride. In certain embodiments, the capsule has a dosage strength of50 mg xanomeline free base and 10 mg trospium chloride. In certainembodiments, the capsule has a dosage strength of 75 mg xanomeline freebase and 20 mg trospium chloride. In certain embodiments, the capsulehas a dosage strength of 75 mg xanomeline free base and 10 mg trospiumchloride. In certain embodiments, the capsule has a dosage strength of125 mg xanomeline free base and 30 mg trospium chloride. In certainembodiments, the capsule has a dosage strength of 125 mg xanomeline freebase and 40 mg trospium chloride.

The present disclosure also provides an oral pharmaceutical composition,comprising: a plurality of xanomeline beads having a size between 0.425mm and 1.18 mm, and core comprising between 30 wt. % and 80 wt. %xanomeline tartrate, between 15 wt. % and 65 wt. % microcrystallinecellulose, and between 0.2 wt. % and 2 wt. % talc; and a plurality oftrospium beads having a size between 0.425 mm and 1.18 mm, and a corecomprising between 8 wt. % and 35 wt. % trospium, between 25 wt. % and80 wt. % microcrystalline cellulose, between 15 wt. % and 70 wt. %lactose monohydrate, and between 0.2 wt. % and 2 wt. % talc; theplurality of xanomeline and the plurality of trospium beads having adissolution rate of more than about 95% within about the first 45minutes following entry of the dosage form into an aqueous solution; andwherein, when administered to a patient for at least 7 days at 20 mgtrospium twice daily, providing a mean C_(max) of trospium at 7850±3360pg/mL and a mean AUC₀₋₁₂ of 41900±15500 hr·pg/mL.

The present disclosure also provides an oral pharmaceutical composition,comprising: a capsule containing a plurality of xanomeline beads and aplurality of trospium beads; the plurality of xanomeline beads having asize between 0.6 mm and 0.85 mm, and a core comprising between 66 wt. %xanomeline tartrate, 33.5 wt. % microcrystalline cellulose, and 0.5 wt.% talc; and the plurality of trospium beads having a size between 0.6 mmand 0.85 mm, and a core comprising 17.7 wt. % trospium chloride, 46.8wt. % microcrystalline cellulose, 35 wt. % lactose monohydrate, and 0.5wt. % talc; the plurality of xanomeline and the plurality of trospiumbeads having a dissolution rate of more than about 95% within about thefirst 20 minutes following the entry of the dosage form into an aqueoussolution; and wherein, when administered to a patient for at least 7days at 20 mg trospium twice daily, providing a mean C_(max) of trospiumat 7850±3360 pg/mL and a mean AUC₀₋₁₂ of 41900±15500 hr·pg/mL.

Further provided is a method of activating muscarinic receptors in abiological sample comprising contacting the biological sample with anyoral pharmaceutical composition described herein.

Also provided is a method for treating a disorder ameliorated byactivating muscarinic receptors in a subject in need thereof, comprisingadministering to a patient in need thereof any oral pharmaceuticalcomposition described herein. In certain embodiments, the subject is ahuman. In certain embodiments, the disorder is selected fromschizophrenia, Alzheimer's disease, Parkinson's disease, depression,movement disorders, pain, drug addiction, tauopathy, andsynucleinopathy.

Further provided is a method of treating a disorder ameliorated byactivating muscarinic receptors in a subject in need thereof, comprisingthe sequential or co-administration of any oral pharmaceuticalcomposition described herein; and a second therapeutic agent.

The present disclosure also provides an oral pharmaceutical composition,comprising xanomeline and/or a salt thereof and less than 0.5 wt. %3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium.Also provided is an oral pharmaceutical composition, comprising aplurality of xanomeline beads comprising xanomeline or a salt thereofand less than 0.5 wt. %3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium;and a plurality of trospium beads comprising a salt of trospium.

The present disclosure further provides an oral pharmaceuticalcomposition, comprising xanomeline and/or a salt thereof and trospiumchloride for treating a muscarinic disorder in a patient in needthereof, wherein when administered to the patient in need thereof, thecomposition is sufficient to provide an in-vivo plasma profilecomprising a median T_(max) for xanomeline of 2 hours and a medianT_(max) for trospium of 1 hour. In certain embodiments, the in-vivoplasma profile further comprises a mean dose-normalized C_(max) ofbetween 48.5 and 121.3 pg/mL/mg and a mean dose-normalized C_(max) oftrospium of between 156 and 375 pg/mL/mg. In certain embodiments, thein-vivo plasma profile further comprises a mean dose-normalized AUC₀₋₁₂of xanomeline of between 263 and 577 hr·pg/mL/mg and a meandose-normalized AUC₀₋₁₂ of trospium of between 881 and 2024 hr·pg/mL/mg.

Further aspects and advantages will be apparent to those of ordinaryskill in the art from a review of the following detailed description.While the dosage form, method of making, and method of treatment aresusceptible of embodiments in various forms, the description hereafterincludes specific embodiments with the understanding that the disclosureis illustrative and is not intended to limit the disclosure to thespecific embodiments described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosure will be readily understood by the following detaileddescription in conjunction with the accompanying drawings, wherein likereference numerals designate like structural elements. The drawingsprovide exemplary embodiments or aspects of the disclosure and do notlimit the scope of the disclosure.

FIG. 1 shows the stability schedule and protocol for xanomeline/trospiumcapsules.

FIG. 2 is a scanning electron microscope (SEM) image of xanomelinetartrate 66% beads at 30× magnification, showing that the beads aresized between 0.6 mm and 0.85 mm used for xanomeline/trospium capsules.

FIG. 3 is an SEM image of trospium chloride 17.7% beads at 30×magnification, showing that the beads are sized between 0.6 mm and 0.85mm used for xanomeline/trospium capsules.

FIG. 4 is the dissolution profile of xanomeline/trospium Cl, 50/20 mgcapsules containing xanomeline beads and trospium Cl beads and measuredat time 0, 1 month, 2 months, 3 months, and 6 months following storageat 40° C./75% RH, as well as 3 months after storage at 25° C./60% RH.

FIG. 5 is the dissolution profile of xanomeline/trospium Cl, 50/10 mgcapsules containing xanomeline beads and trospium Cl beads and measuredat time 0, 1 month, 2 months, and 3 months following storage at 40°C./75% RH as well as 3 months after storage at 25° C./60% RH.

FIG. 6 shows the stability data for xanomeline/trospium Cl, 50/10 mgcapsules stored at 25° C./60% RH and measured at time 0, 3 months, 6months, and 9 months.

FIG. 7 shows the stability data for xanomeline/trospium Cl, 50/10 mgcapsules stored at 30° C./65% RH and measured at time 0, 3 months, and 6months.

FIG. 8 shows the stability data for xanomeline/trospium Cl, 50/10 mgcapsules stored at 40° C./75% RH and measured at time 0, 3 months, and 6months.

FIG. 9 is the dissolution for xanomeline/trospium Cl, 50/10 mg capsulesstored at 25° C./60% RH and measured at time 0, 3 months, 6 months, and9 months.

FIG. 10 is the dissolution profile for xanomeline/trospium Cl, 50/10 mgcapsules stored at 30° C./65% RH and measured at time 0, 3 months, and 6months.

FIG. 11 is the dissolution profile for xanomeline/trospium Cl, 50/10 mgcapsules stored at 40° C./75% RH and measured at time 0, 3 months, and 6months.

FIG. 12 is the xanomeline active pharmaceutical ingredient relatedsubstances profile for xanomeline/trospium Cl 50/10 mg capsules andmeasured at time 0, 3 months, 6 months, and 9 months.

FIG. 13 is trospium chloride active pharmaceutical ingredient relatedsubstances profile for xanomeline/trospium Cl 50/10 mg capsules andmeasured at time 0, 3 months, 6 months, and 9 months.

FIG. 14 is the specification for xanomeline/trospium Cl 50/10 mgcapsules.

FIG. 15 shows the stability data for xanomeline/trospium Cl, 50/20 mgcapsules stored at 25° C./60% RH and measured at time 0, 3 months, and 6months.

FIG. 16 shows the stability data for xanomeline/trospium Cl, 50/20 mgcapsules stored at 30° C./65% RH and measured at time 0 and 6 months.

FIG. 17 shows the stability data for xanomeline/trospium Cl, 50/20 mgcapsules stored at 40° C./75% RH and measured at time 0, 3 months, and 6months.

FIG. 18 is the dissolution for xanomeline/trospium Cl, 50/20 mg capsulesstored at 25° C./60% RH and measured at time 0, 3 months, 6, and 9months.

FIG. 19 is the dissolution profile for xanomeline/trospium Cl, 50/20 mgcapsules stored at 30° C./65% RH and measured at time 0 and 6 months.

FIG. 20 is the dissolution profile for xanomeline/trospium Cl, 50/20 mgcapsules stored at 40° C./75% RH and measured at time 0, 3 months, and 6months.

FIG. 21 is the xanomeline active pharmaceutical ingredient relatedsubstances profile for xanomeline/trospium Cl 50/20 mg capsules andmeasured at time 0, 3 months, and 6 months.

FIG. 22 is trospium chloride active pharmaceutical ingredient relatedsubstances profile for xanomeline/trospium Cl 50/20 mg capsules andmeasured at time 0, 3 months, and 6 months.

FIG. 23 is the specification for xanomeline/trospium Cl 50/20 mgcapsules.

FIG. 24 shows the stability data for xanomeline/trospium Cl, 75/10 mgcapsules stored at 25° C./60% RH and measured at time 0, 3 months, and 6months.

FIG. 25 shows the stability data for xanomeline/trospium Cl, 75/10 mgcapsules stored at 30° C./65% RH and measured at time 0 and 6 months.

FIG. 26 shows the stability data for xanomeline/trospium Cl, 75/10 mgcapsules stored at 40° C./75% RH and measured at time 0, 3 months, and 6months.

FIG. 27 is the dissolution for xanomeline/trospium Cl, 75/10 mg capsulesstored at 25° C./60% RH and measured at time 0, 3 months, and 6 months.

FIG. 28 is the dissolution profile for xanomeline/trospium Cl, 75/10 mgcapsules stored at 30° C./65% RH and measured at time 0 and 6 months.

FIG. 29 is the dissolution profile for xanomeline/trospium Cl, 75/10 mgcapsules stored at 40° C./75% RH and measured at time 0, 3 months, and 6months.

FIG. 30 is the xanomeline active pharmaceutical ingredient relatedsubstances profile for xanomeline/trospium Cl 75/10 mg capsules andmeasured at time 0, 3 months, and 6 months.

FIG. 31 is trospium chloride active pharmaceutical ingredient relatedsubstances profile for xanomeline/trospium Cl 75/10 mg capsules andmeasured at time 0, 3 months, and 6 months.

FIG. 32 is the specification for xanomeline/trospium Cl 75/10 mgcapsules.

FIG. 33 is the dissolution for xanomeline/trospium Cl, 75/20 mg capsulesstored at 25° C./60% RH and measured at time 0, 3 months, and 6 months.

FIG. 34 is the dissolution for xanomeline/trospium Cl, 75/20 mg capsulesstored at 30° C./65% RH and measured at time 0 and 6 months.

FIG. 35 shows the stability data for xanomeline/trospium Cl, 75/20 mgcapsules stored at 40° C./75% RH and measured at time 0, 3 months, and 6months.

FIG. 36 is the dissolution for xanomeline/trospium Cl, 75/20 mg capsulesstored at 25° C./60% RH and measured at time 0, 3 months, and 6 months.

FIG. 37 is the dissolution profile for xanomeline/trospium Cl, 75/20 mgcapsules stored at 30° C./65% RH and measured at time 0 and 6 months.

FIG. 38 is the dissolution profile for xanomeline/trospium Cl, 75/20 mgcapsules stored at 40° C./75% RH and measured at time 0, 3 months, and 6months.

FIG. 39 is the xanomeline active pharmaceutical ingredient relatedsubstances profile for xanomeline/trospium Cl 75/20 mg capsules andmeasured at time 0, 3 months, and 6 months.

FIG. 40 is trospium chloride active pharmaceutical ingredient relatedsubstances profile for xanomeline/trospium Cl 75/20 mg capsules andmeasured at time 0, 3 months, and 6 months.

FIG. 41 is the specification for xanomeline/trospium Cl 75/20 mgcapsules.

FIG. 42 depicts the mean (±standard deviation) xanomelinepharmacokinetic concentrations on Day 1 for KarXT 50/20 twice-dailytreatment for all cohorts of the KAR-003 pharmacokinetic population.

FIG. 43 depicts the mean (±standard deviation) xanomelinepharmacokinetic concentrations by treatment on Day 3 for KarXT 50/20twice-daily treatment for all cohorts of the KAR-003 pharmacokineticpopulation.

FIG. 44 depicts the mean (±standard deviation) xanomelinepharmacokinetic concentrations by treatment on Day 7 for KarXT 50/20twice-daily treatment for all cohorts of the KAR-003 pharmacokineticpopulation.

FIG. 45 depicts the mean (±standard deviation) xanomelinepharmacokinetic concentrations by treatment and visit for the KAR-003pharmacokinetic population.

FIG. 46 depicts the mean (±standard deviation) xanomelinepharmacokinetic trough concentrations by treatment for the KAR-003pharmacokinetic population.

FIG. 47 depict the mean (±standard deviation) trospium pharmacokineticconcentrations on Day 1 for the KarXT 50/20 twice-daily treatment forall cohorts of the KAR-003 pharmacokinetic population.

FIG. 48 depicts the mean (±standard deviation) trospium pharmacokineticconcentrations by treatment on Day 3 for the KAR-003 pharmacokineticpopulation.

FIG. 49 depicts the mean (±standard deviation) trospium pharmacokineticconcentrations by treatment on Day 7 for the KAR-003 pharmacokineticpopulation.

FIG. 50 depicts the mean (±standard deviation) trospium pharmacokineticconcentrations by treatment and visit for the KAR-003 pharmacokineticpopulation.

FIG. 51 depicts the mean (±standard deviation) trospium pharmacokinetictrough concentrations by treatment and visit for the KAR-003pharmacokinetic population.

DETAILED DESCRIPTION

The articles “a” and “an” refer to one or to more than one (i.e., to atleast one) of the grammatical object of the article. By way of example,“an element” means one element or more than one element.

The terms “comprise” and “comprising” are inclusive, open sense, meaningthat additional elements may be included.

The term “consisting” limits the elements to those specified except forimpurities ordinarily associated therewith.

The term “consisting essentially of” limits the elements to thosespecified and those that do not materially affect the basic and novelcharacteristics of the material or steps.

All ranges set forth herein include all possible subsets of ranges andany combinations of such subset ranges. By default, ranges include thestated endpoints, unless stated otherwise, where a range of values isprovided, each intervening value between the upper and lower limit ofthat range and any other stated or intervening value in that statedrange is encompassed within the disclosure. The upper and lower limitsof these smaller ranges may independently be included in the smallerranges and are also encompassed within the disclosure, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both limits, ranges excluding either or both of thoseincluded limits are also contemplated to be part of the disclosure.

The term “wt. %” is the weight percent based on the total weight, e.g.,of the core, or enteric coating, or total bead, as described in context.Unless stated otherwise, the wt. % is intended to describe the weightpercent based on dry weight (e.g., for a core following drying).

The term “controlled release” is defined as a prolonged-release patternof one or more drugs, such that the drugs are released over a period. Acontrolled release formulation has release kinetics that results inmeasurable serum levels of the drug over a period longer than what wouldbe possible following intravenous injection or following administrationof an immediate release oral dosage form. Controlled release,slow-release, sustained-release, extended-release, prolonged-release,and delayed-release have the same definitions herein.

The term “including” means “including but not limited to.” “Including”and “including but not limited to” are used interchangeably.

The term “mammal” is known in the art. Exemplary mammals include humans,primates, bovines, porcines, canines, felines, and rodents (e.g., miceand rats).

The terms “parenteral administration” and “administered parenterally”are art-recognized and refer to modes of administration other thanenteral and topical administration, usually by injection. These modesinclude, without limitation, intravenous, intramuscular, intraarterial,intrathecal, intracapsular, intraorbital, intracardiac, intradermal,intraperitoneal, transtracheal, subcutaneous, subcuticular,intra-articular, subcapsular, subarachnoid, intraspinal, andintrasternal injection and infusion.

A “patient,” “subject,” or “host” to be treated by the subject methodmeans either a human or non-human mammal.

The term “pharmaceutically-acceptable carrier” is art-recognized andrefers to a pharmaceutically-acceptable material, composition, orvehicle, such as a liquid or solid filler, diluent, excipient, solvent,or encapsulating material, involved in carrying or transporting anysubject composition or component thereof from one organ, or portion ofthe body, to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the subjectcomposition and its components and not injurious to the patient. Someexamples of materials that may serve as pharmaceutically acceptablecarriers include sugars, such as lactose, glucose, and sucrose;starches, such as corn starch and potato starch; cellulose and itsderivatives, such as sodium carboxymethyl cellulose, ethylcellulose, andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients,such as cocoa butter and suppository waxes; oils, such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, andsoybean oil; glycols, such as propylene glycol; polyols, such asglycerin, sorbitol, mannitol, and polyethylene glycol; esters, such asethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; phosphatebuffer solutions; and other non-toxic compatible substances employed inpharmaceutical formulations.

The term “pharmaceutically-acceptable salts” is art-recognized andrefers to salts prepared from relatively nontoxic acids or bases,including inorganic acids and bases and organic acids and bases,including, for example, those contained in compositions of the presentdisclosure. Suitable non-toxic acids include inorganic and organic acidssuch as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaricacid, p-toluenesulfonic, hydrochloric, hydrobromic, phosphoric, andsulfuric acids and the like.

The term “treating” is art-recognized and refers to curing as well asameliorating at least one symptom of any condition or disorder.

In jurisdictions that forbid the patenting of methods practiced on thehuman body, the meaning of “administering” of a composition to a humansubject shall be restricted to prescribing a controlled substance that ahuman subject will self-administer by any technique (e.g., orally,inhalation, topical application, injection, insertion, etc.). Thebroadest reasonable interpretation consistent with laws or regulationsdefining patentable subject matter is intended. In jurisdictions that donot forbid the patenting of methods practiced on the human body, the“administering” of compositions includes both methods practiced on thehuman body and the foregoing activities.

The term “therapeutic agent” is art-recognized and refers to anychemical moiety that is a biologically, physiologically, orpharmacologically active substance acting locally or systemically in asubject. Examples of therapeutic agents also referred to as “drugs,” aredescribed in well-known literature references such as the Merck Index(14th edition), the Physicians' Desk Reference (64th edition), and ThePharmacological Basis of Therapeutics (12th edition). These therapeuticagents include without limitation medicaments; vitamins; mineralsupplements; substances used for the treatment, prevention, diagnosis,cure, or mitigation of a disease or illness; substances that affect thestructure or function of the body, or pro-drugs, which becomebiologically active or more active after they have been placed in aphysiological environment.

The term “psychotherapy” refers to non-pharmacological therapies inwhich those skilled in the art use a variety of techniques involvingverbal and other interactions with a patient to affect a positivetherapeutic outcome. Such techniques include, but are not limited to,behavior therapy, cognitive therapy, psychodynamic therapy,psychoanalytic therapy, group therapy, family counseling, art therapy,music therapy, vocational therapy, humanistic therapy, existentialtherapy, transpersonal therapy, client-centered therapy (also calledperson-centered therapy), Gestalt therapy, biofeedback therapy, rationalemotive behavioral therapy, reality therapy, response-based therapy,Sandplay therapy, status dynamics therapy, hypnosis, and validationtherapy. Psychotherapy may involve combining two or more techniques. Atherapist can select and adjust the techniques based on the needs of theindividual patient and the patient's response.

The term “muscarinic disorder” refers to any disease or conditionameliorated by activating the muscarinic system. Such diseases includeones in which direct activation of muscarinic receptors themselves orinhibition of cholinesterase enzymes has produced a therapeutic effect.

The terms “diseases related to schizophrenia” and “disorders related toschizophrenia” include, but are not limited to, schizo-affectivedisorder, psychosis, delusional disorders, psychosis associated withAlzheimer's disease, psychosis associated with Parkinson's disease,psychotic depression, bipolar disorder, bipolar with psychosis,Huntington's disease, Lewy Body dementia, or any other disease withpsychotic features.

The term “movement disorders” includes, but is not limited to, Gilles dela Tourette's syndrome, Friederich's ataxia, Huntington's chorea,restless leg syndrome, and other diseases or disorders whose symptomsinclude excessive movements, tics, and spasms.

The term “mood disorders” includes major depressive disorder, dysthymia,recurrent brief depression, minor depression disorder, bipolar disorder,mania, and anxiety.

The term “cognitive disorders” refers to diseases or disorders marked bya cognitive deficit (e.g., having abnormal working memory,problem-solving abilities, etc.). Diseases include but are not limitedto Alzheimer's disease, Parkinson's Disease, dementia (including, butnot limited to, AIDS-related dementia, vascular dementia, age-relateddementia, dementia associated with Lewy bodies, and idiopathicdementia), Pick's disease, tauopathies, synucleinopathies, confusion,cognitive deficit associated with fatigue, learning disorders, traumaticbrain injury, autism, age-related cognitive decline, and Cushing'sDisease, a cognitive impairment associated with autoimmune diseases.

The term “attention disorders” refers to diseases or conditions markedby having an abnormal or decreased attention span. Diseases include, butare not limited to, attention deficit and hyperactivity disorder (ADHD),attention deficit disorder (ADD), Dubowitz Syndrome, FG Syndrome, Down'sSyndrome, growth delay due to insulin-like growth factor I (IGF1)deficiency, hepatic encephalopathy syndrome, and Strauss Syndrome.

The term “addictive disorders” refers to diseases or conditions markedby addiction or substance dependence as defined by the Diagnostic &Statistical Manual V (DSM-5). Such disorders are characterized byphysical dependence, withdrawal, and tolerance to a substance. Suchsubstances include but are not limited to alcohol, cocaine,amphetamines, opioids, benzodiazepines, inhalants, nicotine,barbiturates, cocaine, and cannabis. Addictive disorders also encompassbehaviors that a patient does compulsively or continually despite clearnegative consequences. For instance, ludomania (gambling addiction orcompulsive gambling) is recognized by those skilled in the art as beingan addictive behavior that often has devastating consequences. Incertain embodiments, the addictive behavior may be Internet GamingDisorder (gaming addiction), as defined in the DSM-5.

The term “pain” refers to physical suffering or discomfort caused byillness or injury. Pain is a subjective experience, and the perceptionof pain is performed as part of the central nervous system (CNS).Usually, noxious (peripheral) stimuli are transmitted to the CNSbeforehand, but the pain is not always associated with nociception. Abroad variety of clinical pain exists, derived from different underlyingpathophysiological mechanisms, and needs different treatment approaches.Three major types of clinical pain have been characterized: acute pain,chronic pain, and neuropathic pain.

Acute clinical pain may result, for example, from inflammation or softtissue injury. This type of pain is adaptive and has the biologicallyrelevant function of warning and enabling healing and repair of analready damaged body part to occur undisturbed. A protective function isachieved by making the injured or inflamed area and surrounding tissuehypersensitive to all stimuli so that contact with any external stimuluscan be avoided. The neuronal mechanisms underlying this type of clinicalpain are well understood, and pharmacological control of acute clinicalpain is available and effective, for example, by means of nonsteroidalanti-inflammatory drugs (NSAIDs) up to opioids depending on the type andextent of the sensation of pain.

Chronic clinical pain appears as sustained sensory abnormalitiesresulting from an ongoing peripheral pathology such as cancer or chronicinflammation (e.g., arthritis), or it can be independent of suchinitiating triggers. Chronic pain independent of initiating triggers ismaladaptive, offering no survival advantage, and very often, noeffective treatment is available.

Neuropathic pain can be classified as peripheral or central. Peripheralneuropathic pain is caused by injury or infection of peripheral sensorynerves, whereas central neuropathic pain is caused by damage to the CNSor/and the spinal cord. Both peripheral and central neuropathic pain canoccur without obvious initial nerve damage.

The term “activator” means a molecule described as an agonist, partialagonist, co-agonist, physiological agonist, potentiator, stimulator,allosteric potentiator, positive allosteric modulator, allostericagonist, or a molecule that increases the activity or signaling ofreceptors directly or indirectly.

The term “inhibitor” means a molecule described as an antagonist,partial antagonist, competitive antagonist, non-competitive antagonist,uncompetitive antagonist, silent antagonist, inverse agonist, reversibleantagonist, physiological antagonist, irreversible antagonist,inhibitor, reversible inhibitor, irreversible inhibitor, negativeallosteric modulator, allosteric antagonist, or a molecule thatdecreases the activity or signaling of receptors directly or indirectly.

The term “maximum tolerated dose” means the highest dose of a drug ortherapeutic that a patient can take without the patient experiencingintolerable side effects. The maximum tolerated dose is typicallydetermined empirically in clinical trials.

The term “muscarinic receptors” refers to G-protein linked receptorsthat bind the neurotransmitter acetylcholine. To date, five subtypes ofthe muscarinic receptor have been identified. “M1” means the subtype onemuscarinic receptor. “M2” means the subtype two muscarinic receptor.“M3” means the subtype three muscarinic receptor. “M4” means the subtypefour muscarinic receptor. “M5” means the subtype five muscarinicreceptor.

The term “antipsychotic” refers to a drug that diminishes psychosis,hallucinations, or delusions. Antipsychotics include, but are notlimited to haloperidol, droperidol, chlorpromazine, fluphenazine,perphenazine, prochlorperazine, thioridazine, trifluoperazine,mesoridazine, periciazine, promazine, triflupromazine, levomepromazine,promethazine, pimozide, chlorprothixene, flupenthixol, thiothixene,zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine,ziprasidone, amisulpride, asenapine, paliperidone, zotepine,aripiprazole, bifeprunox, and tetrabenazine.

The term “anxiolytics” refers to drugs that reduce anxiety, fear, panic,or related feelings. Such drugs include, but are not limited to,benzodiazepines (e.g., alprazolam, chlordiazepoxide, clonazepam,clorazepate, diazepam, lorazepam), buspirone, barbiturates (e.g.,amobarbital, pentobarbital, secobarbital, phenobarbital), andhydroxyzine.

The term “anti-depressants” refers to drugs that alleviate depressionand related conditions (e.g., dysthymia). Such drugs include, but arenot limited to, selective serotonin-reuptake inhibitors (SSRIs, e.g.,citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine,sertraline), serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g.,desvenlafaxine, duloxetine, milnacipran, venlafaxine), mianserin,mirtazapine, norepinephrine reuptake inhibitors (e.g., atomoxetine,mazindol, reboxetine, viloxazine), bupropion, tianeptine, agomelatine,tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin,imipramine, trimipramine, desipramine, nortriptyline, protriptyline),and monoamine oxidase inhibitors (e.g., isocarboxazid, moclobemide,phenelzine, selegiline, tranylcypromine).

The terms “sedatives” or “tranquilizers” refer to drugs that inducesomnolence, promote a feeling of being tired or desire to sleep, orpromote a state of unconsciousness. Such drugs include, but are notlimited to, benzodiazepines, barbiturates (e.g., amobarbital,pentobarbital, secobarbital, phenobarbital), eszopiclone, zaleplon,zolpidem, and zopiclone.

Pharmaceutical Compositions

Earlier development of xanomeline, a muscarinic receptor agonist, asmonotherapy was halted due to peripheral cholinergic side effects. Thecurrent disclosure provides a dosage form with dissolution kineticshaving a more effective therapeutic effect for both active ingredients,enhanced pharmacokinetics for trospium chloride, and greater dosingcompliance. The current disclosure also provides dosage forms withdifferent strengths and/or different ratios of the two actives.

Provided herein is an oral pharmaceutical composition, comprising aplurality of xanomeline beads comprising xanomeline or a salt thereof;and a plurality of trospium beads comprising a salt of trospium. Incertain embodiments, the plurality of xanomeline beads has a corecomprising xanomeline or a salt thereof. In certain embodiments, theplurality of trospium beads has a core comprising a trospium salt.

In certain embodiments, a capsule shell comprising hydroxypropylmethylcellulose (HPMC) containing separate populations of drug beadscontaining xanomeline tartrate or trospium chloride wherein the drugbeads are of comparable size and release the actives rapidly and atsubstantially similar rates. Following the dissolution of the capsuleshell in the stomach, the drug beads may dissolve in the stomach and/orpass through the pyloric valve into the duodenum intact or partiallyintact, but the ratio of the two drugs, both in dissolved form and inundissolved form remains relatively constant in the gastrointestinaltract until the drugs are absorbed.

The formulation for each drug bead allows substantially similarperformance from two actives at different dose ranges, where the activesare released into the blood serum at substantially similar rates and/orachieve a substantially similar T_(max). In certain embodiments, acapsule containing 50 mg xanomeline as the tartrate salt and 10 mgtrospium chloride. Because 50 mg xanomeline as free base corresponds toabout 76 mg xanomeline tartrate, the ratio of the active ingredients insuch a formulation is about 7.6 to 1.

A discrepancy in the number of drug beads in the capsule increases theprobability that the ratio of drug beads would not remain substantiallyconstant after the beads are released and disperse. Thus, in certainembodiments, the trospium beads are formulated with a lower drug loadsuch that effective doses of trospium and of xanomeline are contained inroughly equivalent numbers of beads. In certain embodiments, despite thedifferences in drug loads, the trospium and xanomeline beads release atroughly similar rates. For example, if the dissolution of the capsulesis assessed using a United States Pharmacopeia (USP) dissolutionapparatus, the percentage of xanomeline dissolved is substantiallyequivalent to the percentage of dissolved trospium chloride, such as at10 min, 20 min, or 30 min.

The medicament may also include one or more pharmaceutically acceptablesalts. The medicament may include one or morepharmaceutically-acceptable carriers. The medicament may be administeredorally. The medicament may be delivered orally using tablets, troches,liquids, emulsions, suspensions, drops, capsules, caplets or gel caps,and other methods of oral administration known to one skilled in theart.

The medicament may be in a dosage form that immediately releases thedrug. In an alternative embodiment, the medicament may have a controlledrelease dosage form.

The medicament may be in dosage forms that use other methods ofcontrolled release formulation known to one in the art.

In another embodiment, the medicament is combined with one or moretherapies, including psychotherapy and drugs. Therapeutic agentsinclude, but are not limited, to antipsychotics, anxiolytics,anti-depressants, sedatives, tranquilizers, analgesics, and otherpharmacological interventions known to one skilled in the art. Atherapeutic agent may fall under the category of more than one drug. Forinstance, benzodiazepines can be considered anxiolytics, sedatives, andtranquilizers.

Bead/Core Excipients

The bead and/or core can comprise one or more excipients. In oneembodiment, the excipients include one or more fillers, binders, andsurfactants. Other optional ingredients include, but are not limited to,glidants, lubricants, disintegrants, swelling agents, and antioxidants.The xanomeline or a pharmaceutically acceptable salt thereof and thesalt of trospium may be in separate matrices within the same medicament.

The amount of xanomeline free base in the core can be at least 10 wt. %or at least 15 wt. %, or at least 20 wt. %, or at least 25 wt. %, or atleast 30 wt. %. For example, the amount of xanomeline tartrate can be atleast 50 wt. %, or at least 55 wt. %, or at least 60 wt. %, or at least65 wt. %, or at least 70 wt. %, or at least 75 wt. %, or at least 80 wt.%, or at least 85 wt. % of the core, for example in a range of about 60wt. % to about 90 wt. % or about 65 wt. % to about 85 wt. %. It isunderstood that all ranges including these values as endpoints arecontemplated, for example, at least between about 15 wt. % and about 90wt. %, between about 20 wt. % and about 85 wt. %, between about 30 wt. %and about 85 wt. %, or between about 50 wt. % and about 90 wt. %. Incertain embodiments, the xanomeline beads comprise between 30 wt. % and80 wt. % xanomeline tartrate, such as 66 wt. % xanomeline tartrate.

The amount of trospium salt in the core can be at least 10 wt. % or atleast 15 wt. %, or at least 20 wt. %, or at least 25 wt. %, or at least30 wt. %. For example, the amount of trospium chloride can be at least50 wt. %, or at least 55 wt. %, or at least 60 wt. %, or at least 65 wt.%, or at least 70 wt. %, or at least 75 wt. %, or at least 80 wt. %, orat least 85 wt. % of the core, for example in a range of about 60 wt. %to about 90 wt. % or about 65 wt. % to about 85 wt. %. It is understoodthat all ranges including these values as endpoints are contemplated,for example, at least between about 15 wt. % and about 90 wt. %, betweenabout 20 wt. % and about 85 wt. %, between about 30 wt. % and about 85wt. %, or between about 50 wt. % and about 90 wt. %. In certainembodiments, the trospium is trospium chloride. In certain embodiments,the trospium beads comprise between 8 wt. % and 35 wt. % trospiumchloride, such as 17.7 wt. % trospium chloride.

In a further embodiment, the matrix comprises a polymer, for example, tomodify the release profile of the active in the matrix. In a furtherembodiment, the polymer comprises a water-soluble polymer. In a furtherembodiment, the water-soluble polymer is selected from Eudragit™ RL,polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, andmixtures thereof. In a further embodiment, the polymer comprises awater-insoluble polymer. In a further embodiment, the water-insolublepolymer is selected from Eudragit™ RS, ethylcellulose, celluloseacetate, cellulose propionate, cellulose acetate propionate, celluloseacetate butyrate, cellulose acetate phthalate, cellulose triacetate,poly(methyl methacrylate), poly(ethyl methacrylate), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate),poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenylmethacrylate), poly(methyl acrylate), poly(isopropyl acrylate),poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene),poly(ethylene) low density, poly(ethylene) high density,poly(propylene), poly(ethylene terephthalate), poly(vinyl isobutylether), poly(vinyl acetate), poly(vinyl chloride), polyurethane, andmixtures thereof.

Fillers include, but are not limited to, lactose, saccharose, glucose,starch, microcrystalline cellulose, microfine cellulose, mannitol,sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphoussilica, and sodium chloride, starch, and dibasic calcium phosphatedihydrate. In one embodiment, the filler is not water-soluble, althoughit may absorb water. In one embodiment, the filler is a spheronizationaid. Spheronization aids can include one or more of crospovidone,carrageenan, chitosan, pectinic acid, glycerides, β-cyclodextrin (β-CD),cellulose derivatives, microcrystalline cellulose, powdered cellulose,polyplasdone crospovidone, and polyethylene oxide. In one embodiment,the filler includes microcrystalline cellulose.

The amount of filler in the xanomeline core is not particularly limited.In embodiments, the amount of filler (e.g., microcrystalline cellulose)can be in a range of about 10 wt. % to about 70 wt. %, or about 16 wt. %to about 23 wt. %, or at least 19 wt. % or at least 19.5 wt. %, forexample, about 20 wt. %. In certain embodiments, the xanomeline beadscomprise between 15 wt. % and 65 wt. % microcrystalline cellulose, suchas between about 15 wt. % and 20 wt. %, between about 20 wt. % and 25wt. %, between about 25 wt. % and 30 wt. %, between about 30 wt. % and35 wt. %, between about 35 wt. % and 40 wt. %, between about 40 wt. %and 45 wt. %, between about 45 wt. % and 50 wt. %, between about 50 wt.% and 55 wt. %, between about 55 wt. % and 60 wt. %, or between about 60wt. % and 65 wt. %. In certain embodiments, the xanomeline beadscomprise 33.5 wt. % microcrystalline cellulose.

The amount of filler in the trospium core is not particularly limited.In embodiments, the amount of filler (e.g., microcrystalline celluloseor lactose) can be in a range of about 10 wt. % to about 80 wt. %, orabout 16 wt. % to about 23 wt. %, or at least 19 wt. % or at least 19.5wt. %, for example about 20 wt. %. In certain embodiments, the trospiumbeads comprise between 25 wt. % and 80 wt. % microcrystalline cellulose,such as between about 25 wt. % and 30 wt. %, between about 30 wt. % and35 wt. %, between about 35 wt. % and 40 wt. %, between about 40 wt. %and 45 wt. %, between about 45 wt. % and 50 wt. %, between about 50 wt.% and 55 wt. %, between about 55 wt. % and 60 wt. %, between about 60wt. % and 65 wt. %, between about 65 wt. % and 70 wt. %, between about70 wt. % and 75 wt. %, or between about 75 wt. % and 80 wt. %. Incertain embodiments, the trospium beads comprise 46.8 wt. %microcrystalline cellulose.

In certain embodiments, the trospium beads comprise between 15 wt. % and70 wt. % lactose monohydrate, such as between about 15 wt. % and 20 wt.%, between about 20 wt. % and 25 wt. %, between about 25 wt. % and 30wt. %, between about 30 wt. % and 35 wt. %, between about 35 wt. % and40 wt. %, between about 40 wt. % and 45 wt. %, between about 45 wt. %and 50 wt. %, between about 50 wt. % and 55 wt. %, between about 55 wt.% and 60 wt. %, between about 60 wt. % and 65 wt. %, or between about 65wt. % and 70 wt. %. In certain embodiments, the trospium beads comprise35 wt. % lactose monohydrate.

Binders include, but are not limited to, cellulose ethers,methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropyl cellulose, lower-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose, e.g.,hypromellose 2910, Methocel™ E), carboxymethyl cellulose, starch,pregelatinized starch, acacia, tragacanth, gelatin, polyvinylpyrrolidone (povidone), cross-linked polyvinyl pyrrolidone, sodiumalginate, microcrystalline cellulose, and lower-alkyl-substitutedhydroxypropyl cellulose. In one embodiment, the binders are selectedfrom wet binders. In one embodiment, the binder is selected fromcellulose ethers, e.g., hypromellose.

The amount of binder in the xanomeline core is not particularly limited.In embodiments, the amount of binder (e.g., hypromellose) can be in arange between about 1 wt. % and about 10 wt. %, between about 2 wt. %and about 8 wt. %, or between about 4 wt. % and about 6 wt. %, forexample, about 5 wt. %.

The amount of binder in the trospium core is not particularly limited.In embodiments, the amount of binder (e.g., hypromellose) can be in arange between about 1 wt. % and about 10 wt. %, between about 2 wt. %and about 8 wt. %, or between about 4 wt. % and about 6 wt. %, forexample, about 5 wt. %.

Surfactants include, but are not limited to, anionic surfactants,including sodium lauryl sulfate, sodium deoxycholate, dioctyl sodiumsulfosuccinate, and sodium stearyl fumarate, nonionic surfactants,including polyoxyethylene ethers, and polysorbate 80, and cationicsurfactants, including quaternary ammonium compounds. In one embodiment,the surfactant is selected from anionic surfactants, e.g., sodium laurylsulfate.

The amount of surfactant, e.g., as a processing aid, in the xanomelinecore, is not particularly limited. In embodiments, the amount ofsurfactant (e.g., microcrystalline cellulose) can be in a range betweenabout 0.1 wt. % and about 1 wt. %, between about 0.2 wt. % and about 0.8wt. %, or between about 0.4 wt. % and about 0.6 wt. %, for example,about 0.5 wt. %.

The amount of surfactant, e.g., as a processing aid, in the trospiumcore, is not particularly limited. In embodiments, the amount ofsurfactant (e.g., sodium lauryl sulfate) can be in a range between about0.1 wt. % and about 1 wt. %, between about 0.2 wt. % and about 0.8 wt.%, or between about 0.4 wt. % and about 0.6 wt. %, for example, about0.5 wt. %.

Disintegrants include, but are not limited to, starch, sodiumcross-linked carboxymethyl cellulose, carmellose sodium, carmellosecalcium, cross-linked polyvinyl pyrrolidone, and sodium starchglycolate, low-substituted hydroxypropyl cellulose, and hydroxypropylstarch.

Glidants include, but are not limited to, polyethylene glycols ofvarious molecular weights, magnesium stearate, calcium stearate, calciumsilicate, fumed silicon dioxide, magnesium carbonate, magnesium laurylsulfate, aluminum stearate, stearic acid, palmitic acid, cetanol,stearol, and talc.

Lubricants include, but are not limited to, stearic acid, magnesiumstearate, calcium stearate, aluminum stearate, and siliconized talc. Incertain embodiments, the xanomeline beads comprise between 0 wt. % and 2wt. % talc, such as 0.5 wt. % talc. In certain embodiments, the trospiumbeads comprise between 0 wt. % and 2 wt. % talc, such as 0.5 wt. % talc.

In certain embodiments, the formulation further comprises one or moreantioxidants. Examples of pharmaceutically-acceptable antioxidantsinclude (1) water-soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite,and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metalchelating agents, such as citric acid, ethylenediaminetetra-acetic acid(EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Incertain embodiments, the formulation comprises less than 1 wt. %antioxidant, such as 0.9 wt. %, 0.8 wt. %, 0.7 wt. %, 0.6 wt. %, 0.5 wt.%, 0.4 wt. %, 0.3 wt. %, 0.2 wt. %, 0.1 wt. %, 0.09 wt. %, 0.08 wt. %,0.07 wt. %, 0.06 wt. %, 0.05 wt. %, 0.04 wt. %, 0.03 wt. %, 0.02 wt. %,or 0.01 wt. %. In certain embodiments, the formulation comprises about0.05 wt. % BHT or 0.5 wt. % ascorbic acid. In certain embodiments, theantioxidant is present in the xanomeline core or the xanomeline beads.

In certain embodiments, the xanomeline beads comprise between 30 wt. %and 80 wt. % xanomeline tartrate, between 15 wt. % and 65 wt. %microcrystalline cellulose, and between 0 wt. % and 2 wt. % talc. Incertain embodiments, the trospium beads comprise between 0.2 wt. % and 2wt. % talc, such as 0.5 wt. % talc. In certain embodiments, the trospiumbeads comprise between 8 wt. % and 35 wt. % trospium chloride, between25 wt. % and 80 wt. % microcrystalline cellulose, between 15 wt. % and70 wt. % lactose monohydrate, and between 0.2 wt. % and 2 wt. % talc.

In certain embodiments, the xanomeline tartrate drug beads comprise 66wt. % xanomeline tartrate, 33.5 wt. % microcrystalline cellulose, and0.5 wt. % talc. In certain embodiments, the trospium chloride beadscomprise 17.7 wt. % trospium chloride, 46.8 wt. % microcrystallinecellulose, 35 wt. % lactose monohydrate, and 0.5 wt. % talc. In thisexample, the xanomeline tartrate beads contain about 2.5 times as muchxanomeline as the trospium chloride beads contain trospium chloride.

Depending on dosing requirements, capsules can be prepared withdifferent amounts of xanomeline tartrate and trospium chloride beads. Invarious embodiments, capsules contain 50 mg xanomeline and 10 mgtrospium chloride, 50 mg xanomeline and 20 mg trospium chloride, 75 mgxanomeline and 10 mg trospium chloride, 75 mg xanomeline and 20 mgtrospium chloride, 125 mg xanomeline and 30 mg trospium chloride, or 125mg xanomeline and 40 mg trospium chloride. In certain embodiments, thecapsule contains 25 mg xanomeline as xanomeline tartrate and 10 mgtrospium chloride. In certain embodiments, the capsule contains 50 mgxanomeline as xanomeline tartrate and 10 mg trospium chloride. Incertain embodiments, the capsule contains 50 mg xanomeline as xanomelinetartrate and 20 mg trospium chloride. In certain embodiments, thecapsule contains 75 mg xanomeline as xanomeline tartrate and 10 mgtrospium chloride. In certain embodiments, the capsule contains 75 mgxanomeline as xanomeline tartrate and 20 mg trospium chloride. Incertain embodiments, the capsule contains 125 mg xanomeline asxanomeline tartrate and 20 mg trospium chloride. In certain embodiments,the capsule contains 125 mg xanomeline as xanomeline tartrate and 40 mgtrospium chloride.

In another embodiment, the medicament contains from five milligrams to700 milligrams of xanomeline. In an embodiment, the medicament containsfrom 25 milligrams to 300 milligrams of xanomeline.

In another embodiment, the medicament contains from one milligram to 400milligrams of trospium chloride. In an embodiment, the medicamentcontains from 6.5 milligrams to 200 milligrams of trospium chloride.

In one embodiment, trospium chloride extended-release is used as thetrospium chloride in the medicament. In another embodiment, themedicament contains from one milligram to 400 milligrams of trospiumchloride extended-release. In an embodiment, the medicament containsfrom 6.5 milligrams to 200 milligrams of trospium chlorideextended-release.

In an embodiment, the medicament contains 75 mg or 225 milligrams ofxanomeline, and the same medicament contains 20 mg or 40 milligrams oftrospium chloride. In another embodiment, the medicament contains 75 mgor 225 milligrams of xanomeline, and a different medicament to beco-administered contains 20 mg or 40 milligrams of trospium chloride.

Bead Coatings

In other embodiments, the beads may be coated with functional ornon-functional coatings, for example, for aesthetic, handling, orstability. In certain embodiments, the beads might be coated with apH-sensitive coating so that they do not dissolve in the low pH of thestomach. A nonfunctional coating might be used to maintain chemicalseparation between the beads or for cosmetic reasons.

In a further embodiment, the controlled release formulation comprises asemi-permeable coating. The xanomeline and trospium chloride may be indifferent coatings in the same formulation. In another embodiment, thexanomeline and trospium chloride can be in different coatings indifferent formulations or dosing vehicles. In a further embodiment, thesemi-permeable coating comprises a polymer. In a further embodiment, thecontrolled release formulation comprises a matrix that suspends thexanomeline and trospium chloride.

In certain embodiments, the distribution of coating thicknesses can bestated in the weight gain of coating material based on the total weightof the coated beads. Thus, in one embodiment, the distribution ofcoating thicknesses is at least 2% based on the total weight of thecoated beads. In another embodiment, the distribution of coatingthicknesses is at least 3%. In another embodiment, the distribution ofcoating thicknesses is at least 4%. In another embodiment, thedistribution of coating thicknesses is at least 5%. In anotherembodiment, the distribution of coating thicknesses is at least 6%. Inanother embodiment, the distribution of coating thicknesses is at least7%. In another embodiment, the distribution of coating thicknesses is atleast 8%. In another embodiment, the distribution of coating thicknessesis at least 9%. In another embodiment, the distribution of coatingthicknesses is at least 10%. In another embodiment, the distribution ofcoating thicknesses is at least 11%. In another embodiment, thedistribution of coating thicknesses is at least 12%. In anotherembodiment, the distribution of coating thicknesses is at least 13%. Inanother embodiment, the distribution of coating thicknesses is at least14%.

For example, the difference in coating thickness from bead to bead canbe in a range of +/−1-7% based on the total weight of the coated beads.The distribution of coating thicknesses can between about 2% and about14% based on the weight of the coated beads, such as between about 3%and about 13%, between about 4% and about 12%, between about 5% andabout 11%, between about 6% to about 10%, between about 7% and 9%,between about 3% and 14%, between about 4% and 14%, between about 4% and13%, or between 4% and about 12%.

In one embodiment, the absorption (area under the curve, AUC) of thedosage form when dosed orally is advantageously increased, compared toother dosage forms of xanomeline or trospium chloride. Without intendingto be bound by any theory, the increase in absorption is influenced bythe dosage form exhibiting a pseudo-extended release profile. Thepseudo-extended release profile is influenced by one or more factors,including distribution of coating thicknesses when present, distributionof bead particle sizes, and the beads having irregular bead shapes. Forexample, in an embodiment wherein the beads have a distribution ofcoating thicknesses, for beads with a relatively thin coating, thecoating completely dissolves at the trigger pH relatively quickly torelease the xanomeline and/or trospium chloride compositions, whereasfor beads having a relatively thick coating the coating takes somewhatlonger to completely dissolve and release the xanomeline and/or trospiumchloride compositions. In an embodiment where the beads have adistribution of particle sizes and/or irregular bead shapes, the guttransit time of the beads could be varied due to bead size and/or shape,such that the transit time until reaching the coating dissolution pH isvaried, thus contributing to a pseudo-extended release profile. Inanother embodiment, the dosage form exhibits substantially equivalent(e.g., bioequivalent) C_(max) and/or AUC characteristics whenadministered orally inside a capsule shell or without a capsule shell.

In certain embodiments, the dosage form provides a progressive andpredictable absorption curve. In one embodiment, the T_(max) of thedosage form when dosed orally is more stable on a dose-to-dose basisbecause the beads are individually coated. A predictable, consistentT_(max) is advantageous for accomplishing a more consistent, sustainedtherapeutic effect. For example, process-related variations in coatingthickness or other influences on coating dissolution affect only afraction of the xanomeline and trospium chloride in the dosage form andtend to lead to the pseudo-extended release behavior. In contrast,coated capsules comprising xanomeline and trospium chloride microspheresexhibit significant variability in absorption time from capsule tocapsule.

In certain embodiments, the oral pharmaceutical composition comprisesxanomeline and/or a salt thereof and trospium chloride for treating amuscarinic disorder in a patient in need thereof, which whenadministered to the patient in need thereof, the composition issufficient to provide an in-vivo plasma profile comprising a medianT_(max) for xanomeline of 2 hours and a median T_(max) for trospium of 1hour. In certain embodiments, the in-vivo plasma profile furthercomprises a mean dose-normalized C_(max) of between 48.5 and 121.3pg/mL/mg. In certain embodiments, the in-vivo plasma profile furthercomprises a mean dose-normalized C_(max) of trospium of between 156 and375 pg/mL/mg. In certain embodiments, the in-vivo plasma profile furthercomprises a mean dose-normalized AUC₀₋₁₂ of xanomeline of between 263and 577 hr·pg/mL/mg. In certain embodiments, the in-vivo plasma profilefurther comprises a mean dose-normalized AUC₀₋₁₂ of trospium of between881 and 2024 hr·pg/mL/mg. In certain embodiments, the in-vivo plasmaprofile further comprises a mean C_(max) of trospium at 7850±3360 pg/mL.In certain embodiments, the in-vivo plasma profile further comprises amean AUC₀₋₁₂ of 41900±15500 hr·pg/mL.

In another embodiment, the dosage form exhibits advantageous storagestability, e.g., as measured by the amount of xanomeline presentfollowing storage and/or by the total amount of related substances. Thestorage stability can be assessed following storage at typical ambientconditions (e.g., 25° C. and 60% relative humidity) or at acceleratedstability conditions involving increased temperature and/or humidity.

The dosage form and methods are contemplated to include embodiments ofany combination of one or more of the additional optional elements,features, and steps further described below (including those shown inthe figures and Examples) unless stated otherwise. Reference to a beadand properties thereof apply equally to a collection of beads (e.g., aplurality of such beads). Likewise, a reference to a core and propertiesthereof apply equally to a collection of cores (e.g., a plurality ofsuch cores).

The enteric (gastro-resistant) coating material, e.g., polymer, can beone that will dissolve in intestinal juices at a pH level higher thanthat of the stomach, e.g., a pH of greater than 4.5, such as within thesmall intestine, and therefore permit the release of the activesubstance in the regions of the small intestine and substantially not inthe upper portion of the GI tract. In one embodiment, the entericmaterial begins to dissolve in an aqueous solution at pH between about4.5 and about 5.5. In another embodiment, the enteric material rapidlydissolves in an aqueous solution at a pH of about 5. In anotherembodiment, the enteric material rapidly dissolves in an aqueoussolution at a pH of about 5.5.

For example, pH-sensitive materials do not significantly dissolve untilthe dosage form has emptied from the stomach. The pH of the smallintestine gradually increases from about 4.5 to about 6.5 in theduodenal bulb to about 7.2 in the distal portions of the small intestine(ileum). To provide predictable dissolution corresponding to the smallintestine transit time of about 3 hours (e.g., 2-3 hours) and permitreproducible release therein, the coating should begin to dissolvewithin the pH range of the duodenum and continue to dissolve at the pHrange within the small intestine. Therefore, the amount (thickness) ofenteric coating should be sufficient to be substantially dissolvedduring the about three-hour transit time within the small intestine(e.g., the proximal and mid-small intestine).

Suitable enteric (gastro-resistant) materials include, but are notlimited to, cross-linked polyvinyl pyrrolidone; non-crosslinkedpolyvinylpyrrolidone; hydroxypropylmethyl cellulose phthalate,hydroxypropylmethyl cellulose acetate succinate, cellulose acetatesuccinate; cellulose acetate phthalate, hydroxypropylmethyl celluloseacetate succinate, cellulose acetate trimellitate; starch acetatephthalate; polyvinyl acetate phthalate; carboxymethyl cellulose; methylcellulose phthalate; methyl cellulose succinate; methyl cellulosephthalate succinate; methyl cellulose phthalic acid half ester; ethylcellulose succinate; carboxymethylamide; potassium methacrylatedivinylbenzene copolymer; polyvinyl alcohols; polyoxyethylene glycols;polyethylene glycol; sodium alginate; galactomannan;carboxypolymethylene; sodium carboxymethyl starch; copolymers of acrylicacid and/or methacrylic acid with a monomer selected from the following:methyl methacrylate, ethyl methacrylate, ethyl acrylate, butylmethacrylate, hexyl methacrylate, decyl methacrylate, laurylmethacrylate, phenyl methacrylate, methyl acrylate, isopropyl acrylate,isobutyl acrylate, or octadecyl acrylate, e.g. Eudragit™-L and -Sseries, including L 100-55, L 30 D-55, L 100, S 100, L 12.5, and S 12.5,available from Evonik Industries; polyvinyl acetate; fats; oils; waxes;fatty alcohols; shellac; zein; gluten; ethylacrylate-maleic acidanhydride copolymer; maleic acid anhydride-vinyl methyl ether copolymer;styrol-maleic acid copolymer; 2-ethyl-hexyl-acrylate maleic acidanhydride; crotonic acid-vinyl acetate copolymer; glutaminicacid/glutamic acid ester copolymer; carboxymethylethylcellulose glycerolmonooctanoate; polyarginine; poly(ethylene); poly(propylene);poly(ethylene oxide); poly(ethylene terephthalate); poly(vinyl isobutylether); poly(vinyl chloride); and polyurethane. A combination of entericmaterials may also be used. In one embodiment, the enteric materialrapidly dissolves at pH 5.5 and higher to provide fast dissolution inthe upper bowel. For example, the enteric material can be selected froma copolymer of methacrylic acid and methyl methacrylate and a copolymerof methacrylic acid and ethyl acrylate. For example, an enteric polymeris poly(methacrylic acid co-ethyl acrylate) 1:1 (Eudragit™ L 30 D-55 andEudragit™ L 100-55).

Other suitable examples of enteric coating coatings include beeswax andglyceryl monostearate; beeswax, shellac and cellulose; and cetylalcohol, mastic and shellac, and shellac and stearic acid; polyvinylacetate and ethyl cellulose; and neutral copolymer of polymethacrylicacid esters (Eudragit™ L 30D); copolymers of methacrylic acid andmethacrylic acid methylester, or a neutral copolymer of polymethacrylicacid esters containing metallic stearates. Such coatings comprisemixtures of fats and fatty acids, shellac and shellac derivatives, andthe cellulose acid phthalates, e.g., those having a free carboxylcontent.

One or more plasticizers can be added to enteric polymers to increasetheir pliability and reduce brittleness, as known in the art. Suitableplasticizers include, for example, butyl citrates, triethyl citrate,diethyl phthalate, dibutyl sebacate, polyethylene glycols (PEGs, such asPEG 6000), acetyl triethyl citrate, and triacetin. In one embodiment,the plasticizer is triethyl citrate. While some enteric materials areflexible and do not require plasticizers, more brittle polymers (e.g.,Eudragit™ L/S types, Eudragit™ RL/RS, and Eudragit™ FS 30 D) benefitfrom plasticizers, for example ranging from between 5 wt. % and 30 wt. %based on the dry polymer mass, between about 8 wt. % and about 12 wt. %triethyl citrate with poly(methacrylic acid co-ethyl acrylate) 1:1.

In certain embodiments, the enteric coatings comprise one or moreanti-tacking agents (antiadherents) to reduce the tackiness of the filmand prevent agglomeration, as it is known in the art. Suitableanti-tacking agents include, but are not limited to talc, glycerylmonostearate, fumed silica (e.g., Aerosil™ 200), precipitated silica(e.g., Sipernat™ PQ), and magnesium stearate. Anti-tacking agents can beused in any suitable quantity, for example ranging between about 10 wt.% and 100 wt. % based on dry polymer mass, between about 10 wt. % andabout 50 wt. %, between about 10 wt. % and about 30 wt. %, or betweenabout 15 wt. % and about 30 wt. %. For example, in one embodiment, itranges between 15 wt. % and about 30 wt. % based on dry polymer mass.

One or more surfactants can also be added to an enteric coating mixtureto increase substrate wettability and/or stabilize suspensions, as it isknown in the art. Surfactants include Polysorbate 80, sorbitanmonooleate, and sodium dodecyl sulfate, and other surfactants describedherein.

The enteric coating can be formed by any suitable process. Coatingprocesses include pan coating, fluid bed coating, and dry coating (e.g.,heat dry coating and electrostatic dry coating), for example. Pancoating and fluid bed coating using solvent are well-establishedprocesses. In liquid coating, the enteric material and optionalexcipients (e.g., pigments, plasticizers, anti-tacking agents) are mixedin an organic solvent or water to form a solution or dispersion. Thecoating solution or dispersion is sprayed into solid dosage forms in apan coater or a fluid bed dryer and dried by hot air. For example, in aWurster fluid bed coating process, the coating fluid is sprayed from thebottom of the fluid bed apparatus. Alternatively, the coating fluid isapplied by top spraying. In certain embodiments, a tangential spray isapplied.

The amount of enteric material applied is sufficient to achieve thedesired acid resistance and release characteristics. For example, in oneembodiment, the amount of enteric coating meets USP <711> requirements(USP 36-NF 31) for delayed-release dosage forms, thereby not releasing10.0 wt. % of the drug after 2 hours in 0.1 N HCl. In certainembodiments, the formulation releases at least 80% of the active in 20minutes in pH 6.8 buffer solution, e.g., using a dissolution method ofUSP 36-NF 31 section <711>.

In one embodiment, the enteric coating is present in an amount in arange between about 10% and 40%, or between 25% and about 35% asmeasured by the weight gain compared to the uncoated particle cores, orranging between about 25% and about 31% weight gain, between about 27%and about 31% weight gain, or between about 28.5% and about 31% weightgain, based on the weight of the uncoated particle cores.

The formulation can include a capsule shell in which the beads aredisposed. Soft and hard capsule shells are known. In one embodiment, thecapsule shell is a hard-capsule shell, e.g., a gelatin capsule shell ora vegetable-based hard capsule shell. In certain embodiments, thecapsule shell comprises one or more enteric coatings described herein.During accelerated storage, gelatin capsules may collapse. Thus, incertain embodiments, the formulation can include ahydroxypropylmethylcellulose capsule shell.

Thus, for example, one embodiment combining various of the featuresdescribed above includes a pharmaceutical dosage form comprising aplurality of xanomeline beads, the beads comprising a core comprisingxanomeline tartrate, a filler (optionally microcrystalline cellulose), abinder (optionally hypromellose), and an enteric coating (optionallyEudragit™ L 30 D-55) surrounding the core, wherein the plurality ofbeads has a distribution of particle sizes ranging between about 0.7 mmand about 2.5 mm, wherein the enteric coating ranges between about 20%and about 40% based on the weight of the bead cores, and wherein thebeads are disposed in a capsule shell.

Bead Size and Shape

The plurality of beads has a distribution of particle sizes. Theplurality of beads has bead shapes. The plurality of beads has adistribution of coating thicknesses when present.

Beads having a distribution of particle sizes were shown to exhibitadvantageous pharmacokinetics. Without intending to be bound by anytheory, it is contemplated that the pharmacokinetics are influenced bythe plurality of beads having a distribution of core sizes.

In one embodiment, the particle sizes of the beads range between about0.4 mm and about 1.2 mm, such as between about 0.4 mm and about 0.5 mm,between about 0.5 mm and about 0.6 mm, between about 0.6 mm and about0.7 mm, between about 0.7 mm and about 0.8 mm, between about 0.8 mm andabout 0.9 mm, between about 0.9 mm and about 1.0 mm, between about 1.0mm and about 1.1 mm, or between about 1.1 mm and about 1.2 mm. Incertain embodiments, the size of the xanomeline beads is between about0.425 mm and about 1.18 mm. In certain embodiments, the size of thexanomeline beads is between about 0.6 mm and about 0.85 mm. In certainembodiments, the size of the trospium beads is between about 0.425 mmand about 1.18 mm. In certain embodiments, the size of the trospiumbeads is between about 0.6 mm and about 0.85 mm.

The beads or bead mixtures may be used, for example, in suspensions,filled into capsules, compressed into tablets, or filled into sachets.One or more types of modified release beads can be mixed together andencapsulated or used as a sprinkle on the subject's food. In certainembodiments, the oral solid dosage form may be any of these forms. Incertain embodiments, the dosage form is a capsule.

As the particle size of the beads becomes too small, the variability inthe content of the active increases. As the particle size becomes toolarge, the beads are too large for drug products labeled to beadministered via sprinkling (e.g., on applesauce or other soft foods,such as jellies) and swallowed without chewing or administered via anenteral feeding tube. Also, as the particle size increases, the largerparticles get coated more than the smaller particles, resulting in lowerrelative assay compared to smaller particles. To compensate, relativelymore beads are needed to meet the label strength per capsule. Filling acapsule shell with sufficient large particles to meet the label strengthper capsule becomes difficult or impossible (e.g., to fill a size 0capsule to a 75-mg strength of xanomeline free base).

In one embodiment, the beads are formulated into capsules, e.g., with anencapsulation machine. Various capsule sizes may accommodate thestrength and fill weight of the target formulations. Capsule size rangesfrom 00 to 5 for fill weights ranging between about 15 mg and about 630mg.

The beads can be sorted (e.g., via sieving) to the desired particlesize. In certain embodiments, the particle size range is any particlesize range or combination thereof described above regarding the cores.In one embodiment, the particle size range is the same as the particlesize range of the uncoated cores. For example, the beads can be sievedsuch that 5% or less of the bead cores by weight is retained on a #12mesh (1.68 mm) screen, and 10% or less by weight pass through a #20 mesh(0.84 mm) screen.

Method of Making

Provided is a method for preparing an oral pharmaceutical compositioncomprising admixing beads comprising a plurality of xanomeline beadscomprising xanomeline or a pharmaceutically acceptable salt thereof witha plurality of trospium beads comprising a salt of trospium, such astrospium chloride. In certain embodiments, the method further comprisesformulating the admixed beads into capsules.

Also disclosed herein are a method for preparing the dosage form,comprising coating a core comprising xanomeline or a pharmaceuticallyacceptable salt thereof and an excipient with an enteric polymer to formthe enteric coating, and coating a core comprising trospium chloride ora pharmaceutically acceptable salt thereof and an excipient with anenteric polymer to form the enteric coating. Optionally, the core can beformed by a wet granulation method. Optionally, drug beads are sorted(e.g., via sieving) to a desired particle size range before entericcoating, and optionally again following enteric coating.

The drug beads may be made by different processes, including, but notlimited to, spheronizing an extruded wet mass and coating of inert corespheres in a fluidized bed. In certain embodiments, the beads areprepared by extrusion and spheronization.

The beads are formulated to flow freely and to be compatible with modernencapsulation equipment. In some embodiments, the beads are blendedtogether to form a uniform mixture that can be filled into capsules in asingle stage. In other embodiments, the beads are filled separately intocapsules using a two-stage capsule filler.

The cores comprising xanomeline or pharmaceutically acceptable saltsthereof can be formed by any suitable process. In one embodiment, thecore is formed by granulating a mixture of xanomeline or apharmaceutically acceptable salt thereof with an excipient and millingto a desired particle size range. In another embodiment, the core can beformed by extrusion and spheronization of a mixture of xanomeline or apharmaceutically acceptable salt thereof with an excipient.

The cores comprising trospium chloride or pharmaceutically acceptablesalts thereof can be formed by any suitable process. In one embodiment,the core is formed by granulating a mixture of trospium chloride or apharmaceutically acceptable salt thereof with an excipient and millingto a desired particle size range. In another embodiment, the core can beformed by extrusion and spheronization of a mixture of trospium chlorideor a pharmaceutically acceptable salt thereof with an excipient.

Granulating processes can include fluid bed granulation, wetgranulation, hot melt granulation, and spray congealing, for example.Other processes include slugging and roller compaction. The mixtures tobe granulated can first be dry-blended. The dry-blended dry ingredientscan be mixed with water before extrusion.

Extrusion and spheronization of a mixture of xanomeline or apharmaceutically acceptable salt thereof and trospium chloride with anexcipient provide desirable cores with a distribution of particle sizesas described herein and one or more other desirable properties. Incertain embodiments, short processing times can lead to a more stableproduct. For example, reducing spheronization reduces friction andrelated heat. Reducing the time that the product is exposed to air(either when moist and/or before packaging) also diminishes oxidation.On the other hand, rapid processing by extrusion and spheronization canlead to a poor-quality product, for example, in having a large fractionof the bead cores falling outside a desired particle size range. Themoisture absorbed by spheronization aids (which happens over time)influences the spheronization characteristics of the beads.

Accordingly, in one embodiment, the moisture content of the granulationmixture, before drying, ranging between about 20 wt. % and about 40 wt.%, such as between 25 wt. % and about 35 wt. %, between about 28 wt. %and about 32 wt. %, at least about 28 wt. %, at least about 28.5,between about 20 wt. % and about 40 wt. %, between about 25 wt. % andabout 35 wt. %, between about 27 wt. % and about 31 wt. %, or betweenabout 28.5 wt. % and about 31 wt. %.

In certain embodiments, the wet mass can be held before extrusion, forexample, to allow the spheronization aid to swell with granulatingfluid. The hold time can be at least 15 minutes, such as at least 30minutes, at least 45 minutes, or at least 60 minutes. In certainembodiments, the hold time ranging between about 15 minutes and about120 minutes, such as between about 30 minutes and 100 minutes, orbetween 60 minutes and 90 minutes.

As described above relating to cores, the method can include a step ofsorting (e.g., by sieving) the cores before optional coating to retainparticles in a predetermined size range, for example, sizes rangingbetween about 0.7 mm and about 2.8 mm, such as between about 0.7 mm andabout 2.5 mm, between about 0.8 mm and about 1.7 mm, or any rangedescribed herein.

As described above relating to beads, the method can include a step ofsorting (e.g., by sieving) the beads after optional coating to retainparticles in a size range, for example, sizes ranging between about 0.7mm and about 2.8 mm, such as between about 0.7 mm and about 2.5 mm, orbetween about 0.8 mm and about 1.7 mm, or any range described herein.

In an extrusion and spheronization process, the following optionalfeatures can be employed, individually or in one or more combinationsthereof. Water can be a granulation agent. Microcrystalline cellulosecan be in the cores as a spheronization aid. Hypromellose can beincluded in the cores as a binder. The extrusion screen size can be 1.0mm. The friction plate of the spheronizer can be cross-hatched. Thefriction plate of the spheronizer can be cross-hatched with a squarepitch of at least about 3 mm, or greater than about 3 mm, or at leastabout 4 mm, or greater than about 4 mm, or ranging between about 3 mmand about 7 mm, or about 5 mm. The spheronization time can be less thanabout 5 minutes, or less than about 4 minutes, or less than about 3minutes, or less than about 2 minutes, or up to 1 minute. Thespheronized particles can include non-spherical particles (i.e.,irregular shapes), for example, a substantial fraction thereof, such asat least about 20 wt. %, at least about 30 wt. %, at least about 40 wt.%, at least about 50 wt. %, at least about 60 wt. %, or at least about70 wt. % thereof.

In certain embodiments, the pharmaceutical composition is stored with adesiccant, for example, pharmaceutical grades of silica gel, crystallinesodium, potassium or calcium aluminosilicate, colloidal silica,anhydrous calcium sulfate, and the like.

In certain embodiments, the pharmaceutical composition is stored with anoxygen absorber.

In certain embodiments, the pharmaceutical composition is stored under adry inert gas such as nitrogen, helium, argon, neon, xenon, krypton, ora mixture thereof.

In certain embodiments, the pharmaceutical composition is stored underreduced pressure in comparison with the external ambient air.

In certain embodiments, the pharmaceutical composition is stored at areduced temperature, e.g., at refrigerated temperatures (e.g., 2° C. to8° C.). In certain embodiments, the pharmaceutical composition is storedin such a manner that has fewer impurities, such as Impurity A, thanwhen stored at 25° C.

In certain embodiments, the pharmaceutical composition is stored by amanufacturer, a distributor, a pharmacy, or a hospital at a temperatureof between about 2° C. and about 8° C. prior to dispensing the oralpharmaceutical composition to the subject. In certain embodiments, afterthe oral pharmaceutical composition is dispensed to the subject, thepharmaceutical composition is stored at a temperature of between about20° C. and about 25° C.

Also provided is a method of stabilizing a pharmaceutical dosage form orcomposition as described herein, comprising storing the dosage form at atemperature of about 2° C. to about 8° C.

In certain embodiments, a method for preparing a pharmaceutical dosageform comprising xanomeline beads comprises forming a wet mass comprisingxanomeline tartrate and an excipient, optionally microcrystallinecellulose, with a moisture content ranging between about 20 wt. % andabout 40 wt. %, extruding and spheronizing the wet mass comprisingxanomeline tartrate and excipient to make cores, sorting the cores to atarget particle size range, optionally between about 0.7 mm and about2.5 mm, coating the sorted cores with a polymer to form beads comprisinga core and a coating, and sorting the bead particles to a targetparticle size range, optionally between about 0.7 mm and about 2.5 mm.

In certain embodiments, a method for preparing a pharmaceutical dosageform comprising trospium beads comprises forming a wet mass comprisingtrospium chloride and an excipient, optionally microcrystallinecellulose, with a moisture content ranging between about 20 wt. % andabout 40 wt. %, extruding, spheronizing, and drying the wet masscomprising trospium chloride and excipient to make cores, sorting thecores to a target particle size range, optionally between about 0.7 mmand about 2.5 mm, coating the sorted cores with a polymer to form beadscomprising a core and a coating, and sorting the bead particles to atarget particle size range, optionally between about 0.7 mm and about2.5 mm.

Purity

Also provided is the compound3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium.

Also provided is a pharmaceutical composition, comprising xanomelineand/or a salt thereof and less than 0.5 wt. %3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium(Impurity A). In certain embodiments, the pharmaceutical compositioncomprises less than 0.30 wt. % of Impurity A, such as less than 0.25 wt.%, less than 0.20 wt. %, less than 0.15 wt. %, less than 0.14 wt. % orless than 0.1 wt. %. Also provided is a pharmaceutical composition,comprising xanomeline and/or a salt thereof and less than 0.15 wt. %3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium(Impurity A).

Also provided is an oral pharmaceutical composition, comprising aplurality of xanomeline beads comprising xanomeline or a salt thereofand less than 0.5 wt. %3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium;and a plurality of trospium beads comprising a salt of trospium. Alsoprovided is an oral pharmaceutical composition, comprising a pluralityof xanomeline beads comprising xanomeline or a salt thereof and lessthan 0.15 wt. %3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium;and a plurality of trospium beads comprising a salt of trospium.

In certain embodiments, the pharmaceutical composition comprises lessthan 0.5 wt. % of Impurity A after the pharmaceutical composition isstored for at least 3 months at 40° C. and 75% relative humidity.

In certain embodiments, the total impurities in the pharmaceuticalcompositions provided herein are no greater than about 5% by weight, nogreater than about 4% by weight, no greater than about 3% by weight, nogreater than about 2.5% by weight, no greater than about 2% by weight,no greater than about 1.5% by weight, no greater than about 1% byweight, no greater than about 0.5% by weight, or no greater than about0.1% by weight.

Method of Treating

Further provided a method of activating muscarinic receptors in abiological sample, the method comprising contacting the biologicalsample with any oral pharmaceutical composition described herein. Alsoprovided is a method for treating a disorder ameliorated by activatingmuscarinic receptors in a subject in need thereof, comprisingadministering to the subject in need thereof any oral pharmaceuticalcomposition described herein.

While activators of M1 and M4 muscarinic receptors have been suggestedto be efficacious treatments for schizophrenia, the activation ofmuscarinic receptors located outside the brain has resulted in sideeffects that barred xanomeline from the clinic. For instance, in bothPhase I and subsequent trials, the muscarinic agonist xanomeline hadunacceptable GI and other side effects linked to the binding ofmuscarinic receptors in the body's periphery. By combining a xanomelinewith trospium chloride, the desired therapeutic effect is achieved whilediminishing or eliminating the side effects associated with activatingmuscarinic receptors located outside the brain.

The tolerability of xanomeline, a muscarinic activator, is increased byco-administering trospium chloride, a muscarinic antagonist. The mostcommon adverse events observed with administering xanomeline are nausea,vomiting, diarrhea, excessive sweating, and excessive salivation(so-called cholinergic adverse events). The disclosed compositionsreduced the incidence of these adverse events in humans, evincingincreased xanomeline tolerability.

In one embodiment, xanomeline is combined with trospium chloride totreat muscarinic disorders, ameliorating symptoms in response tomuscarinic activation by xanomeline in living tissues found outside thebrain. In an embodiment, such diseases or disorders includeschizophrenia and diseases related to schizophrenia, cognitive disordersin neurodegenerative diseases such as Alzheimer's, and pain such asnociceptive pain or neuropathic pain. The combination of xanomeline andtrospium chloride is a safer method for treating those diseases shown tobe responsive to activation of muscarinic receptors.

In another embodiment, xanomeline and trospium chloride treat mooddisorders. In another embodiment, xanomeline and trospium chloride treatmovement disorders. In another embodiment, xanomeline and trospiumchloride treat cognitive disorders, including enhancing cognitivefunction not associated with a specific pathology. In anotherembodiment, xanomeline and trospium chloride treat attention disorders.In another embodiment, xanomeline and trospium chloride treat pain.Outside disease treatment, enhancing attention accelerates learning anddecreases fatigue due to both lack of sleep and circadian rhythmdisturbances, such as jet lag. In another embodiment, xanomeline andtrospium chloride treat addictive disorders.

In one embodiment, xanomeline combined with trospium chloride treats ananimal. In a further embodiment, the animal is a mammal. In anembodiment, the mammal is a human being.

In one embodiment, trospium chloride decreases the side effectsassociated with xanomeline. Such side effects include, but are notlimited to, GI side effects, cardiac side effects, excessive sweating,and excessive salivation. Use of trospium with xanomeline allows thexanomeline to be used clinically when the xanomeline would not otherwisebe used clinically due to its side effects. In another embodiment, useof trospium chloride with the xanomeline allows for the xanomeline toachieve a higher maximum tolerated dose than xanomeline would otherwiseachieve.

Various time and resource-intensive methods demonstrated the efficacy ofthe combination of xanomeline and trospium chloride. For example, animalmodels demonstrate the efficacy of new therapeutics for schizophrenia,including both pharmacological models (e.g., ketamine model) and geneticmodels (e.g., DISC1 mouse). Likewise, animal models, including rodents,dogs, and non-human primates, demonstrate the side effect profile ofpharmacological agents. Animal models are an experimental proxy forhumans but may suffer from deficiencies in the physiological differencesbetween humans and animals and thus may have limited predictive powerfor human experiments, particularly for central nervous systemdisorders. Alternatively, the disclosed combination can be tried incontrolled clinical trials of people. Standard measures based on patientself-report can be used by those skilled in the art to assess variousside effects such as GI discomfort. As another example, objectivephysiological measures (e.g., EKGs) may be used by those skilled in theart. A set of standard measures has also been developed to assessschizophrenia symptoms, including the Brief Psychiatric Rating Scale(BPRS), the Positive and Negative Syndrome Scale (PANSS), and ClinicalGlobal Impression (CGI). Typically, clinical trials are double-blinded,where one group of patients receives an inactive placebo, and the othergroup the active intervention.

Before administering the claimed combinations, patients may have alead-in period from one to fourteen days, during which lead-in periodtrospium chloride is given alone. In one embodiment, the trospiumchloride is administered for one or more dose periods beforeadministering xanomeline to accumulate trospium chloride in the body orfor the trospium chloride to reach or approach steady-state exposurelevels. This accumulation, or higher exposure levels of the trospiumchloride, increases the blockade of muscarinic receptors outside of thebrain and reduces adverse events when xanomeline is administered. Inanother embodiment, the trospium chloride is administered for one ormore days before xanomeline.

In one embodiment, xanomeline and trospium chloride are administered toa patient 6 times during a 24-hour period. In another embodiment,xanomeline and trospium chloride are administered to a patient 5 timesduring a 24-hour period. In another embodiment, xanomeline and trospiumchloride are administered to a patient 4 times during a 24-hour period.In an embodiment, xanomeline and trospium chloride are administered to apatient 3 times during a 24-hour period. In another embodiment,xanomeline and trospium chloride are administered to a patient twiceduring a 24-hour period. In another embodiment, xanomeline and trospiumchloride are administered to a patient once during a 24-hour period.

In one embodiment, an extended-release formulation of trospium chlorideis used in combination with xanomeline. In another embodiment, trospiumchloride extended-release is administered to a patient from one time tofive times during a 24-hour period. In an embodiment, trospium chlorideextended-release is administered from one to three times during a24-hour period. In another embodiment, from five milligrams to 400milligrams of trospium chloride, extended-release is used during a24-hour period. In an embodiment, from 20 milligrams to 200 milligramsof trospium chloride, extended-release is used during a 24-hour period.

In one embodiment, 225 mg xanomeline and 40 mg trospium chloride areadministered to a patient in a 24-hour period. In another embodiment,100 mg xanomeline and 20 mg trospium chloride are administered to apatient in a 24-hour period. In another embodiment, 125 mg xanomelineand 20 mg trospium chloride are administered to a patient in a 24-hourperiod. In another embodiment, 125 mg xanomeline and 30 mg trospiumchloride are administered to a patient in a 24-hour period. In anotherembodiment, 125 mg xanomeline and 40 mg trospium chloride areadministered to a patient in a 24-hour period. In another embodiment,200 mg xanomeline and 40 mg trospium chloride are administered to apatient in a 24-hour period. In another embodiment, 200 mg xanomelineand 80 mg trospium chloride are administered to a patient in a 24-hourperiod. In another embodiment, 250 mg xanomeline and 60 mg trospiumchloride are administered to a patient in a 24-hour period. In anotherembodiment, 250 mg xanomeline and 80 mg trospium chloride areadministered to a patient in a 24-hour period. In another embodiment,300 mg xanomeline and 40 mg trospium chloride are administered to apatient in a 24-hour period. In another embodiment, 300 mg xanomelineand 80 mg trospium chloride are administered to a patient in a 24-hourperiod.

Treatment may be initiated with smaller dosages. Thereafter, the dosagemay be increased by small increments until a balance between therapeuticeffect and side effects is attained. While the subject is being treated,the health of the patient may be monitored by measuring one or more ofthe relevant indices at predetermined times during the treatment period.Treatment, including composition, amounts, times of administration, andformulation, may be adjusted per such monitoring. The patient may beperiodically reevaluated to determine improvement by measuring the sameparameters. Adjustments to the disclosed composition administered andpossibly to the time of administration may be made based on thesereevaluations.

EXAMPLES

The following examples are provided for illustration and are notintended to limit the scope of the disclosure.

Example 1—Immediate Release Beads

Beads were prepared for xanomeline tartrate (Table 1) and trospiumchloride (Table 2).

TABLE 1 Xanomeline tartrate (66%) Bead without Talc Ingredient % w/w(dry basis) g/batch Xanomeline tartrate  66  99 Microcrystallinecellulose  34  51 Purified water*  (30)  (45) Total: 100 150 *Removedduring drying.

TABLE 2 Trospium chloride (17.7%) Bead without Talc Ingredient % w/w(dry basis) g/batch Trospium chloride 17.7 17.7 Microcrystallinecellulose 35   35   Lactose monohydrate 47.3 47.3 Purified water* (45)  (45)   Total: 100   100   *Removed during drying.

The powders were screened using Quadro Comil Model 197 equipped with457-μm round hole screen, 0.2-inch spacer at 1625 rpm and mixed for 2min in a Hobart low shear mixer/granulator (model N-50) at a fixed speedof 60 rpm. The dry blending step is optional, as blend uniformity isdriven by subsequent wet granulation. Beads were screened by handthrough a 40 mesh (425 μm) sieve.

Wetting was carried out in the Hobart. The water was added using aCole-Parmer peristaltic pump. Water addition rate (amount of water/dosetime) is a process variable.

The wet mass was extruded through a perforated screen (domeconfiguration) single screw extruder using an LCI Multi Granulator MG-55at 30 rpm (shaft speed). The wet mass was extruded directly afterwetting. Hold time, shaft speed, and extrusion rate (load) were processvariables.

The extrudates were placed into an LCI Marumerizer (spheronizer) QJ-230Tequipped with a 2.0 mm friction plate. The extrudates were spheronizedat different plate speeds for a total of not more than 4 minutes.Spheronization speed and time are process variables.

The beads were dried using an Aeromatic™ Strea-1 fluid bed at an inlettemperature of 60° C. until a water content of not more than 3% wasobtained. Because beads melted after a few minutes at 60° C., the beadswere dried at 30° C.

Water content was evaluated gravimetrically by loss-on-drying (LOD)using a Mettler Toledo Halogen Moisture Analyser, type HR83. The beadswere heated at 105° C. until the rate of weight loss dropped to less orequal to 0.0% within 60 seconds.

TABLE 3 Extrusion/Spheronization Process Parameters Xanomeline tartrateTrospium chloride Parameter (66% w/w) (17.7% w/w) Wet massing Powder (g)150 100 Water (g) 45 45 % (w/w) dry basis 30 45 Dose time (min) 3 3Total massing time (min) 3.5 3.5 Liquid rate (g/min) 15 17 ExtrusionHold time (min) 0 0 Die hole size (mm) 0.8 0.8 Shaft speed (rpm) 30 30Load (Ap) 2.3 2.2-2.4 Spheronization Plate speed (rpm)  900/1500 900Spheronization time (min) 1/1 2 Drying Inlet Temp.(° C.) 60 60 OutletTemp. (° C.) NMT 53 NMT 53 Drying time (min) 75 30 LOD (%) 3.5 2.5

Example 2—Scaling Up Immediate Release Bead Formulations

The beads from Example 1 were scaled-up with and without talc (Tables4-7). Extrusion/Spheronization process parameters are shown in Table 8.

TABLE 4 Xanomeline Tartrate (66%) Beads Without Talc % w/w Ingredient(dry basis) g/batch Xanomeline tartrate  66  660 Microcrystallinecellulose  34  340 Purified water* (24) (240) Total: 100 1000 *Removedduring drying.

TABLE 5 Xanomeline tartrate (66%) Bead with Talc Ingredient Purpose %w/w (dry basis) g/batch Xanomeline tartrate Active 66.0 3,465.0Microcrystalline cellulose Binder, 33.5 1758.75 (USP, Ph. Eur.)disintegrant Purified water* (USP) Granulating (30.0) (1575.0) fluidTalc (USP, Ph. Eur.) Glidant 0.5 26.25 Total 100.0 5,250.0Abbreviations: Ph. Eur = European Pharmacopeia, USP = United StatesPhaimacopeia *Evaporated during the process thus not included in totalweight

TABLE 6 Trospium Chloride (17.7%) Beads Without Talc Ingredient % w/w(dry basis) g/batch Trospium chloride  17.7  88.7 Microcrystallinecellulose  35 175.0 Lactose monohydrate  47.3 236.3 Purified water* (59)(295) Total: 100 500 *Removed during drying.

TABLE 7 Trospium chloride (17.7%) Bead with Talc % w/w IngredientPurpose (dry basis) g/batch Trospium chloride (USP) Active 17.7 593.6Microcrystalline cellulose Binder, 46.8 1567.15 (USP, Ph. Eur.)disintegrant Lactose monohydrate (NF) Filler 35.0 1,172.5 Purifiedwater* (USP) Granulating (47.0) (1574.5) fluid Talc (USP, Ph. Eur.)Glidant 0.5 16.75 Total 100 3,350.0 Abbreviations: NF = NationalFormulary, Ph. Eur = European Pharmacopeia, USP = United StatesPharmacopeia. *Evaporated during process

TABLE 8 Extrusion/Spheronization Process Parameters Xanomeline tartrateTrospium chloride Parameter (66% w/w) (17.7% w/w) Wet massing Powder (g)1000 500 Water (g) 240 295 % (w/w) dry basis 24 59 Dose time (min) 3 4Total massing time (min) 3.5 4.5 Liquid rate (g/min) 80 82 ExtrusionHold time (min) 0 0 Die hole size (mm) 0.8 0.8 Shaft speed (rpm) 30 30Load (Ap) 2.2-2.3 2.4-2.5 Spheronization Plate speed (rpm) 900 900Spheronization time (min) 0.5 1 Drying Inlet Temp. (° C.) 60 60 OutletTemp. (° C.) NMT 50 NMT 49 Drying time (min) 50 40 LOD (%) 2.3 2.4

Example 3—Capsule Stability and Dissolution Testing

Capsules were produced by weighing beads and filling them into HPMCcapsules manually. Beads were encapsulated by hand using an Accofil™capsule filling machine where beads premixed with talc (0.5%) werefilled individually/one-after-the-other in the capsule, as shown inTable 9.

TABLE 9 Composition of Xanomeline/Trospium Chloride Capsules.Ingredients are listed in milligrams per capsule. 25 mg/ 50 mg/ 50 mg/75 mg/ 75 mg/ Ingredient Function 10 mg 10 mg 20 mg 10 mg 20 mgXanomeline drug beads Active ingredient 58.1 116.1 116.1 174.2 174.2Xanomeline tartrate Drug substance 38.3 76.6 76.6 115.0 115.0 [totalweight (25.0) (50.0) (50.0) (75.0) (75.0) (freebase)] Microcrystallinecellulose Binder, 19.5 38.9 38.9 58.4 58.4 (USP, Ph.Eur.) disintegrantTalc (USP, Ph. Eur.) Glidant 0.3 0.6 0.6 0.9 0.9 Trospium drug beadsActive ingredient 56.5 56.5 113.0 56.5 113.0 Trospium chloride (USP)Drug substance 10 10 20 10 20 Microcrystalline cellulose Binder, 26.426.4 52.9 26.4 52.9 (USP, Ph. Eur.) disintegrant Lactose monohydrate, NFFiller 19.8 19.8 39.6 19.8 39.6 Talc (USP, Ph. Eur.) Glidant 0.3 0.3 0.60.3 0.6 HPMC capsule shell Capsule 95.6 95.6 95.6 95.6 95.6Hydroxypropyl methyl- Structure 93.7 93.7 93.7 93.7 93.7 cellulose (USP,Ph. Eur.) Titanium dioxide Colorant 1.9 1.9 1.9 1.9 1.9 (USP, Ph. Eur.)Total 210.2 268.2 324.7 326.3 382.8

After drying, the beads were screened by shaking for 5 min through 16mesh (1.18 mm) and 40 mesh (0.425 mm) screens. The beads in size betweensieves 1.18 mm and 0.425 mm were retained for further analysis.

The morphology and surface characteristics of beads were examined byscanning electron microscopy (SEM) using a JSM-6010LV InTouchScope™(JEOL Ltd, Tokyo, JP) microscope with a back-scattered electron detector(BES). Samples were placed on metallic stubs using double-sided carbonconductive tape. The images were obtained with accelerating voltages of20 kV under low vacuum (60 Pa) and magnification 30×.

Bulk and tapped density were determined in duplicate using the USP <616>method using a tapped density tester (JV 1000, Copley Scientific). Thebulk density was measured from the volume of a known mass of powdersample in a graduated cylinder. The tapped density was measured bymechanically tapping the measuring cylinder until the volume changed nofurther.

The powder flow properties were evaluated using Carr's CompressibilityIndex and Hausner ratio. Both were derived using the measured values forbulk and tapped density. Carr's Compressibility Index (CI) wascalculated using bulk and tapped density data when fitted into theequation: Compressibility Index=(Tapped density−Bulk density)/Tappeddensity×100%. Hausner Ratio (H) was calculated as the ratio of tapped tobulk density. Capsules were analyzed for appearance, assay, relatedsubstances, water content, and dissolution. FIG. 1 shows the stabilityschedule and protocol for xanomeline/trospium capsules.

The beads were further sized between 0.6 mm and 0.85 mm. Some beadsexhibited similar morphological properties. Modifications in some otherbeads decreased the density of beads and led to rough surfaces and lossof sphericity. Scanning electron microscope (SEM) images of xanomelinetartrate 66% beads (FIG. 2) trospium chloride 17.7% beads (FIG. 3) at30× magnification showed that the beads are sized between 0.6 mm and0.85 mm. These beads were used in xanomeline/trospium capsules. Particlesize distribution (PSD) of beads was determined by mechanical sieving.As shown in Table 10, most beads for both APIs were sized between 0.425and 1.18 mm.

TABLE 10 Particle Size Distribution by Mechanical Sieving of Beads %Retained Sieve No. (opening 66% Xanomeline 17.7% Trospium diameter)tartrate chloride 16 mesh (1.18 mm) 8.1 0.4 40 mesh (0.425 mm) 90.6 97.3Receiver 1.3 2.3 Total: 100 100

Table 11 shows the densities and flow properties of beads collectedbetween 0.425 mm and 1.18 mm sieves. Xanomeline tartrate and trospiumchloride IR beads showed different densities and flow properties, whichcan be critical when mixing bead systems.

TABLE 11 Density and Flow Properties of 0.425-1.18 mm Beads Bulk Tappeddensity density Carr Hausner Sample ID (g/cm³) (g/cm³) Index (%) RatioXanomeline tartrate (66%) 0.59/0.58 0.63/0.62 7/7 1.08/1.08 beads -Example 1 Xanomeline tartrate (66%) 0.54/0.54 0.58/0.57 6/6 1.07/1.07beads - Scale up Trospium chloride (17.7%) 0.81/0.80 0.83/0.83 2/31.02/1.04 beads - Example 1 Trospium chloride (17.7%) 0.78/0.790.81/0.82 3/3 1.03/1.03 beads - Scale up

The analysis in Table 12 shows favorable results for assay and relatedsubstances and moisture content for 50 mg xanomeline and 20 mg trospiumchloride capsules. Data in Table 13 show that these attributes wereretained during storage stability studies. Similar data are provided forthe 50 mg xanomeline and 10 mg trospium chloride capsules in Table 14.Dissolution data for these two dosage forms are provided in Table 15 andTable 16. Other tables showing stability for the xanomeline/trospiumchloride formulations are shown in FIGS. 6-41.

TABLE 12 Analytical Results Formulation Trospium Chloride/ TrospiumChloride/ Xanomeline Tartrate Xanomeline Tartrate Beads in CapsulesBeads in Capsules Dose strength 20 mg salt Trospium 10 mg salt TrospiumChloride Chloride 50 mg Xanomeline 50 mg Xanomeline free base free baseDescription White opaque capsules White opaque capsules Assay Trospiumchloride Trospium chloride (% LC) 98.9% (n = 2: 99.2, 98.5) 97.1% (n =2: 97.1, 97.1) Xanomeline free base Xanomeline free base 99.4% (n = 2:100.1, 98.8) 100.6% (n = 2: 100.3, 101.0) Related No impurities ≥0.1% LCNo impurities ≥0.1% LC Substances (% LC) Moisture 2.4% 2.2% (KF) (% w/w)

TABLE 13 Stability of KarXT 50/20 Description T = 0 White opaquecapsules T = 1 m, 40° C./75% RH No change from initials T = 2 m, 40°C./75% RH No change from initials T = 3 m, 25° C./60% RH No change frominitials T = 3 m, 40° C./75% RH No change from initials T = 6 m, 40°C./75% RH No change from initials Assay (% LC) T = 0 Trospium chloride:98.9 (99.2, 98.5) Xanomeline free base: 99.4 (100.1, 98.8) T = 1 mTrospium chloride 40° C./75% RH 100.4 (97.8, 103.1) Xanomeline freebase: 101.7 (101.6, 101.8) T = 2 m Trospium chloride: 40° C./75% RH 98.2(98.7, 97.7) Xanomeline free base: 99.3 (100.3, 98.3) T = 3 m Trospiumchloride: 25° C./60% RH 99.1 (99.7, 98.4) Xanomeline free base: 102.0(103.7, 100.3) T = 3 m Trospium chloride: 40° C./75% RH 98.4 (98.5,98.3) Xanomeline free base: 99.9 (99.8, 100.0) T = 6 m Trospiumchloride: 40° C./75% RH 96.0 (95.6, 96.4) Xanomeline free base: 97.8(97.6, 98.1) Related T = 0 No impurities ≥0.1% LC Substances T = 1 m,40° C./75% RH No impurities ≥0.1% LC (% LC) T = 2 m, 40° C./75% RH 0.14%T = 3 m, 25° C./60% RH No impurities ≥0.1% LC T = 3 m, 40° C./75% RH0.14% T = 6 m, 40° C./75% RH 0.2% Moisture (KF) T = 0 2.4% (% w/w) T = 1m, 40° C./75% RH 3.0% USP <921> T = 2 m, 40° C./75% RH 3.3% Method Ia T= 3 m, 25° C./60% RH 2.7% T = 3 m, 40° C./75% RH 2.6% T = 6 m, 40°C./75% RH 3.4%

TABLE 15 Assay and Related Substances of KarXT 50/10 Description T = 0White opaque capsules T = 1 m, 40° C./75% RH No change from initials T =2 m, 40° C./75% RH No change from initials T = 3 m, 25° C./60% RH Nochange from initials T = 3 m, 40° C./75% RH No change from initialsAssay (% LC) T = 0 Trospium chloride: 97.1 (97.1, 97.1) Xanomeline freebase: 100.6 (100.3, 101.0) T = 1 m Trospium chloride: 40° C./75% RH 98.5(98.2, 98.9) Xanomeline free base: 102.7 (104.4, 101.1) T = 2 m Trospiumchloride: 40° C./75% RH 96.7 (95.7, 97.6) Xanomeline free base: 98.8(99.3, 98.3) T = 3 m Trospium chloride: 25° C./60% RH 98.5 (96.5, 100.5)Xanomeline free base: 99.2 (98.2, 100.1) T = 3 m Trospium chloride: 40°C./75% RH 98.1 (97.6, 98.6) Xanomeline free base: 99.4 (99.0, 99.8)Related T = 0 No impurities ≥0.1% LC Substances T = 1 m, 40° C./75% RHNo impurities ≥0.1% LC (% LC) T = 2 m, 40° C./75% RH 0.14% T = 3 m, 25°C./60% RH No impurities ≥0.1% LC T = 3 m, 40° C./75% RH 0.14% Moisture(KF) T = 0 2.2% (n = 2: 2.4, 2.1) (% w/w) T = 1 m, 40° C./75% RH 2.1% (n= 2: 2.4, 1.9) USP <921> T = 2 m, 40° C./75% RH 2.2% (n = 3: 1.8, 2.4,2.4) Method Ia T = 3 m, 25° C./60% RH 2.1% (n = 3: 1.9, 2.4, 2.1) T = 3m, 40° C./75% RH 2.5% (n = 3: 2.3, 2.6, 2.4)

Subsequent testing showed that KarXT 50/10, 50/20, and 75/20 inhard-shell capsules were stable for at least 12 months 25° C./60% RH.Based on available data, a shelf-life of 15 months at 25° C./60% RH isproposed.

The dissolution results show that the two compounds release quickly,which may increase their bioavailability, and that they also release atcomparable rates despite substantial differences in compositions betweenthe two bead formulations. Both xanomeline and trospium chloride havelow bioavailabilities, and rapid release can increase bioavailability byoverwhelming saturable processes that limit absorption into the generalcirculation.

An unknown xanomeline impurity with a relative retention time of about1.09 was observed during stability studies of the combination drugproducts. The impurity was first observed during testing at thethree-month time point for the 50 mg xanomeline/10 mg trospium chloridedrug product and at the initial time point for the other threecombination products, both of which occurred at the same time. Theimpurity peak increased both with time and with increasing storagetemperature. The impurity had not been observed before the presentstudies.

Preliminary studies suggest that the RRT 1.09 impurity is3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium(C₁₄H₂₀N₃O₂S⁺, MW=294.1271 Da):

The RRT 1.09 impurity is a hydroxylated version of Compound V(C₁₄H₂₀N₃OS⁺, MW=278.1322 Da), which is the penultimate intermediate inthe synthesis of xanomeline with negative mutagenic potential:

To reduce the presence of the impurity, the storage temperature for thedrug product was lowered. Bottles were flushed with argon to minimizeheadspace oxygen during packaging. In certain embodiments, thexanomeline bead formulation was formulated with an antioxidant, such as0.5 wt. % ascorbic acid or 0.05 wt. % BHT.

Example 4—KAR-001 Phase I Study of Combination of Xanomeline andTrospium Chloride

A Phase I, double-blind, randomized multiple-dose pilot study wasconducted with xanomeline administered alone compared to xanomelineadministered with trospium chloride in normal healthy volunteers. Theprimary objectives of this study were (1) to assess the safety andtolerability of administering, for 7 days, 225 mg daily of xanomelinewith 40 mg daily of trospium chloride, versus administering 225 mg dailyof xanomeline alone for 7 days; and (2) to determine whether addingtrospium 40 mg daily (20 mg BID) to xanomeline 225 mg daily (75 mg TID)over 7 days significantly reduces peripheral cholinergic side effects(nausea, diarrhea, vomiting, sweating, excess salivation) versusxanomeline 225 mg daily, alone. Table 17 lists the parameters from thisstudy.

TABLE 17 Parameters of the KAR-001 study Sample Size: N = 70 subjectsStudy Population: Normal healthy volunteers; ages 18-60 Study Duration:Treatment: Nine days; a two-day run-in period of either placebo ortrospium 40 mg/day, followed by 7 days of active treatment Follow-up: 14days following discharge from the clinic Test product, Xanomeline, 75 mgcapsules, TID, for a 225-mg total daily dose dose, and mode Trospiumchloride, 20 mg tablet, over-encapsulated, for a 40-mg total ofadministration: daily dose, BID. Matching placebo. Study Design Thestudy was an inpatient study conducted in normal healthy volunteers.Between study days −21 to −7, normal healthy volunteers visited theclinic to receive and sign Informed Consent and undergo screeningprocedures. Patients entered the clinic on Study Day 0 for baselinesafety assessment and enrollment in the study. On the morning of StudyDay 1 subjects began administration of study drug. Subjects randomizedto the xanomeline-only arm received placebo for the first two days, andbegan TID xanomeline treatment on Day 3. Subjects randomized to thexanomeline + trospium arm received BID trospium chloride for the firsttwo days, and then TID xanomeline plus BID trospium starting on Day 3.Matching placebo was administered to maintain the blind. Patientsremained in clinic under observation for the full duration of treatment(9 days). Main criteria for Age 18-60 inclusion: Female subjects had tobe postmenopausal (at least 2 years prior to dosing) or agree to use anacceptable form of birth control from screening until 14 days aftercompletion of the study. If on birth control pills, had to have been ona stable dose for ≥12 months. Good general health Ability to giveinformed consent and understand verbal instructions. Willingness tospend 10 days in an in-patient facility. Main criteria for History orpresence of clinically significant cardiovascular, pulmonary, exclusion:hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic,dermatologic, neurologic, oncologic, or psychiatric disease or any othercondition that, in the opinion of the investigator, would jeopardize thesafety of the subject or the validity of the study results. (Subjectswith any history of resolved cancer that was >5 years passed could beincluded.) Body Mass Index <18 or >40 kg/m² History of or high risk ofurinary retention, gastric retention, or narrow- angle glaucoma. Historyof alcohol or drug abuse within the last 24 months, or current abuse asdetermined by urine toxicology screen. Clinically significant abnormalfinding on the physical exam, medical history, ECG, or clinicallaboratory results at screening. Had participated in another clinicaltrial within 90 days before the first dose of study medication. Neededto take any prescription medication besides the investigational productor those specifically noted above. Use of any vitamins, herbs,supplements, or over-the-counter medications are excluded within oneweek of enrollment, and during the trial. Specifically, subjects werenot permitted to take Benadryl ® for one week prior to and during thestudy. Use of any tobacco products within the past 30 days. Previouspositive test for HIV 1 and/or 2, or Hepatitis A, B, or C, or a positivetest obtained at screening. Selected Treatment emergent signs andsymptoms (adverse event incidence rates). Endpoints: Cholinergictreatment emergent signs and symptoms (salivation, sweating, nausea,vomiting, diarrhea) (cholinergic adverse event incidence rates). Theseadverse events were observed at high rates in past xanomeline studiesand were drivers of subject discontinuation.

Seventy total study subjects were randomized, and of these, 68 studysubjects received at least one assessment on day 3, which was the firstday of xanomeline administration. Table 18 lists the demographics of thestudy subjects.

TABLE 18 Demographics of the KAR-001 study subjects Xanomeline aloneXanomeline + Trospium Characteristic (N = 33) (N = 35) Age (years; Mean[SD]) 34.8 [8.8]  40.9 [12.3] Gender (M/F; [%]) 21/12 27/8  64%/36%77%/23% Race (White/  9/24 13/21 Non-White; [%]) 27%/70% 37%/60% Weight(kg; Mean [SD])  88 [17]  88 [16] BMI (kg/m2; Mean [SD]) 29.1 [5.0] 28.8[5.0]

The most common adverse events with xanomeline are the so-calledcholinergic adverse events of nausea, vomiting, diarrhea, excessivesweating, and excessive salivation. In this study, the co-administrationof trospium chloride with xanomeline led to a statistically significant(p=0.016) 43% reduction in the incidence rate of cholinergic adverseevents compared to xanomeline co-administered with placebo. In thexanomeline+placebo arm of the study, 63% of subjects reported at leastone cholinergic adverse event, compared to only 34% of subjectsreporting such an event in the xanomeline+trospium chloride arm of thestudy.

Further, in the study, each kind of individual cholinergic adverse eventalso had a decreased incidence rate in subjects administeredxanomeline+trospium chloride, compared to the incidence rate in subjectsadministered xanomeline+placebo. The decrease in the incidence rate ofsweating was statistically significant on its own, at 20.0% in thexanomeline+trospium chloride arm, down from 48.5% in thexanomeline+placebo arm, which was a 59% reduction (p=0.013).

The overall cholinergic adverse event rate in the xanomeline+trospiumchloride arm of the study was very similar to the 32% incidence ratereported during the two-day run-in period for subjects onplacebo+placebo. Although these two data points did not occur duringdifferent periods of the study, the fact that the cholinergic adverseevent rate was comparable to that of placebo suggests that the 43%reduction in adverse events due to trospium chloride may have been closeto the maximum reduction possible in this study.

Table 19 shows the incidence and number of cholinergic adverse events inthe evaluable population of the study were as follows, with all p-valuesbased on a chi-squared test, except those marked with an *, which werebased on a Fisher's exact test.

TABLE 19 Cholinergic adverse events Xanomeline + Xanomeline + placeboTrospium (n = 34) (n = 35) (n [%] (n [%] P-value for % Category [# ofevents]) [# of events]) difference Reduction Any 21 (63.6%) 64 12(34.3%) 33 0.0155 46% TEAEs Nausea  8 (24.2%) 11  6 (17.1%) 8 0.4693 29%Vomiting  5 (15.2%) 5  2 (5.7%) 2 0.2522* 62% Diarrhea  7 (21.2%) 8  2(5.7%) 4 0.0794* 73% Sweating 16 (48.5%) 24  7 (20.0%) 8 0.0131 59%Salivation 12 (36.4%) 16  9 (25.7%) 11 0.342 39%

In addition to evaluating whether adding trospium chloride increased thetolerability of xanomeline, the study also provided data about theoverall safety and tolerability of xanomeline+trospium chloride. Table20 shows that overall the combination was well tolerated with no severeadverse events and no serious adverse events, and with most adverseevents being mild.

TABLE 20 Tolerability Xanomeline + placebo Xanomeline + TrospiumCategory (n (%) # events) (N = 33) (N = 35) Subjects with any TEAE 27(81.8) 108 23 (65.7) 73 Max Severity of TEAE Mild 22 (66.7) N/A 20(57.1) N/A Moderate  5 (15.2) N/A  3 (8.6) N/A Severe  0 (0.0)  0 (0.0)Any clinically  5 (15.2) 5  3 (8.6) 6 significant TEAE Any study drug-23 (69.7) 92 18 (51.4) 57 related TEAE Max severity of studydrug-related TEAE Mild 19 (57/6) N/A 15 (42.9) N/A Moderate  4 (12.1)N/A  3 (8.6) N/A Severe  0 (0.0) N/A  0 (0.0) N/A Any SAE  0 (0.0)  0(0.0) AE leading to  2 (6.1) 2  1 (2.9) 1 discontinuation (D/C) Studydrug related AE  1 (3.0) 1  0 (0.0) leading to D/C

The tolerability profile found in this study allowed future studies ofthe combination of xanomeline and trospium chloride to proceed.

Example 5—KAR-003 Phase I Study of KarXT, a Xanomeline+Trospium CombinedFormulation

This study was a Phase 1, randomized, multiple-dose, adaptive design,inpatient study to assess the safety and tolerability of KarXT in normalhealthy volunteers aged 18 to 60 years. Subjects signed the informedconsent and underwent Screening assessments on Days −21 to −1. Uponsuccessfully completing all Screening assessments, subjects returned tothe study clinic on Day 0 for baseline safety assessments and enrollmentinto the study and were randomized 3:1 in each cohort into one of twotreatment arms: KarXT or placebo. Subjects were assigned to 1 of 4cohorts (Cohort 1, 2, 3, or 4).

The study drug was administered BID on Days 1 through 7. A combinationdosage formulation of both xanomeline and trospium was used in allcohorts. All cohorts began with a 2-day lead-in of KarXT 50/20 BID (forsubjects randomized to active treatment); after the 2-day lead-inperiod, the unblinded pharmacist dispensed the study drug to eachsubject per the subject's randomization assignment for 5 days ofspecified cohort dosing, for a total of 7 days of treatment. Matchingplacebo was administered throughout the study to maintain the blind. Asentinel group was introduced to the study for Cohorts 2 to 4 and wasmonitored for safety and tolerability by the Data Safety EvaluationGroup (DSEG), such that about 30% of the proposed cohort was treated andassessed for safety before the rest of the cohort was dosed. Subjectsand study clinic staff were blinded to treatment. The Dose SelectionCommittee (DSC) was unblinded to decide dosing for subsequent treatmentgroups.

Serial blood samples for the PK assessment of xanomeline and trospiumwere drawn on Days 1, 3, and 7. More blood was sampled at routineintervals for monitoring trough concentrations of xanomeline andtrospium and clinical laboratory assessments. On Day 1, saliva volumewas collected twice. A saliva volume was measured predose on Day 1 andthen daily (afternoon) on Days 1 through 7 at about the same time of dayto avoid diurnal variations. Other assessments included pupil sizemeasurements and Bristol stool scale assessments. Subjects remained inthe study clinic for the full duration of treatment (7 days). Followinga safety assessment on Day 8, subjects were discharged from the studyclinic and asked to return about 14 days after administration of thestudy drug for a final safety assessment.

During the study, following the 2-day lead-in of KarXT 50/20 BID (forsubjects randomized to active treatment) in each cohort, subjects weredosed as follows:

-   -   In Cohort 1, subjects completed Days 3 through 7 of dosing of        KarXT 100/20 BID (total daily dose (TDD) of 200 mg xanomeline        plus 40 mg trospium) or placebo.    -   In Cohort 2, the sentinel group (Group 2a) discontinued dosing        after the Day 4 morning dose. The dosage for subjects in Cohort        2 was KarXT 150/20 BID (TDD of 300 mg xanomeline plus 40 mg        trospium) or placebo. Dosing of Cohort 2 was discontinued (DSEG        decision based on observed tolerability concerns). The study        proceeded to dosing of the Cohort 3 sentinel group (Group 3a) as        the DSC determined that further dosing of Cohort 2 with KarXT        150/20 BID was unlikely to be tolerated well enough to warrant        further developing this dose combination for a clinical        population.    -   In Cohort 3, the sentinel group (Group 3a) completed Days 3        through 7 of dosing of KarXT 150/40 BID (TDD of 300 mg        xanomeline plus 80 mg trospium) or placebo. The second group in        Cohort 3 (Group 3b) discontinued dosing after the Day 5 morning        dose.    -   In Cohort 4, the sentinel group (Group 4a), the second group        (Group 4b), and the remaining group (Group 4c) completed Days 3        through 7 of dosing of KarXT 125/40 BID (TDD of 250 mg        xanomeline plus 80 mg trospium) or placebo.

Ninety-six subjects were planned, 248 subjects were screened, 69subjects were randomized, 51 subjects completed the study, and 18subjects discontinued the study. The population included male and femalehealthy subjects aged 18 to 60 years at screening with a body mass indexof 18 to 40 kg/m′. Subjects were excluded from the study if they had ahistory of irritable bowel syndrome or serious constipation requiringtreatment within 6 months before Screening. Subjects were also excludedfrom the study if they had a history or presence of any disease orcondition, including psychiatric or neurological diseases that, in theInvestigator's opinion, would have jeopardized the subject's safety orthe study's validity. Table 21 summarizes the demographics and baselinecharacteristics by treatment group. The demographic and baselinecharacteristics were consistent between the Safety Population and the PKPopulation.

TABLE 21 Summary of Demographics and Baseline Characteristics byTreatment Group-Safety Population Cohort 2 Cohort 3 Cohort 4 Cohort 1KarXT KarXT KarXT Characteristic KarXT 150/20 BID 150/40 BID 125/40Category/Statistic 100/20 BID [1] [2] BID Placebo Total n 18 5 12 18 1669 Mean (SD) 42.0 (12.9) 39.0 (8.80) 38.2 (9.4) 39.8 (9.56) 37.9 (10.61)39.6 (10.51) Gender-n (%) Male 11 (61.1) 3 (60.0) 5 (41.7) 9 (50.0) 13(81.3) 41 (59.4) Female 7 (38.9) 2 (40.0) 7 (58.3) 9 (50.0) 3 (18.8) 28(40.6) Race-n (%) White 8 (44.4) 1 (20.0) 7 (58.3) 6 (33.3) 4 (25.0) 26(37.7) Black or African American 9 (50.0) 4 (80.0) 5 (41.7) 12 (66.7) 12(75.0) 42 (60.9) Asian 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)American Indian 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) orAlaska Native Native Hawaiian 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0(0.0) or Other Pacific Islander Other 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) 0(0.0) 1 (1.4) Ethnicity-n (%) Hispanic or Latino 2 (11.1) 1 (20.0) 2(16.7) 2 (11.1) 1 (6.3) 8 (11.6) Not Hispanic or Latino 16 (88.9) 4(80.0) 10 (83.3) 16 (88.9) 15 (93.8) 61 (88.4) Baseline weight (kg) Mean(SD) 81.8 (15.0) 81.0 (12.1) 81.3 (13.6) 73.5 (8.9) 77.6 (10.3) 78.5(12.2) Baseline height (cm) Mean (SD) 172.5 (9.5) 168.8 (5.8) 170.7(10.1) 166.1 (6.8) 172.1 (8.8) 170.1 (8.8) Baseline body mass index(kg/m²) Mean (SD) 27.4 (3.8) 28.4 (3.8) 27.8 (3.7) 26.7 (3.2) 26.3 (3.7)27.1 (3.6) 1. Cohort 2 sentinel group (5 subjects randomized to KarXT150/20 BID and 1 subject randomized to placebo) was discontinued afterthe Day 4 morning dose. 2. During the study, Cohort 3 Group 3b (8subjects randomized to KarXT 150/40 BID and 1 subject randomized toplacebo) was discontinued after the Day 5 morning dose.

Serial blood samples for assessing the PK of xanomeline and trospiumwere collected from all subjects in each cohort on Days 1, 3, and 7before the morning dose and at 1, 2, 3, 4, 6, 8, 10, and 12 hours afterthe morning dose. The PK parameters listed below were calculated fromthe individual xanomeline and trospium concentration-time profiles bystandard non-compartmental methods. Dose-normalized parameters werecalculated for C_(max) and area under the concentration-time curve (AUC)values. During the study, additional blood samples for monitoring troughconcentrations of xanomeline and trospium were collected on Days 2, 4,5, and 6 before the morning dose and before discharge on Day 8.

Safety evaluations included spontaneously reported adverse events, ECGs,laboratory assessments, vital signs, assessments of saliva volumes,Bristol stool scale, pupil size, and physical examinations. Descriptivestatistics (n, mean, standard deviation, median, minimum, and maximum)summarized the continuous data by treatment group. Geometric mean (GM),geometric percent coefficient of variation (CV %), quartiles, or boxplots were generated. The count and frequency tabulated categoricalmeasurements, although formal statistics were not conducted.

Treatment groups were summarized as follows unless otherwise specified:KarXT 50/20 BID (for adverse events and Day 1 PK summaries only), KarXT100/20 BID, KarXT 125/40 BID, KarXT 150/20 BID, KarXT 150/40 BID, andplacebo (Empty Vcaps® Plus Capsules and Capsugel®; all cohort placebogroups combined). The safety evaluation was based on spontaneouslyreported adverse events, ECGs, laboratory assessments, and vital signs.Exploratory analyses of saliva volumes, Bristol stool scale, and pupilsize were also conducted.

Xanomeline was well absorbed into the systemic circulation followingoral administration of the KAR-003 formulation at all dosages. Peakconcentrations of xanomeline were observed at a median time of 2 hoursacross all treatment groups and study days.

Median t_(1/2) values for xanomeline were similar between treatmentgroups and across study days, indicating that t_(1/2) was notdose-dependent. Median t_(1/2) ranged from 3.4 to 5.8 hours.

GM xanomeline exposures did not increase dose-proportionally on Day 3from 100 to 150 mg when xanomeline was administered with 20 mg trospiumor from 125 to 150 mg when administered with 40 mg trospium. Lowerxanomeline exposures were observed following treatment with KarXT 150/40compared to KarXT 125/40. Day 3 GM xanomeline exposures (C_(max),AUC_(0-last), and AUC_(0-12 hr)) were similar when the 150 mg xanomelinedose was administered with 20 and 40 mg trospium. On Day 7, GMxanomeline exposures increased slightly more than dose-proportionallyfrom 125 to 150 mg when xanomeline was administered with 40 mg trospium.

Minimal to no xanomeline accumulated in plasma from Day 3 to Day 7following treatment with KarXT 100/20 BID and KarXT 125/40 BID; however,there was accumulation following administration of KarXT 150/40 BID in 3of the 4 subjects who completed the study. The mean accumulation ratiosfor the KarXT 150/40 BID group were 366.2% for RAUC and 445.4% forRC_(max).

Example 6—Xanomeline Pharmacokinetics of KAR-003 Compared to KAR-001

Comparing xanomeline GM exposures between KAR-001 (75 mg xanomelineTID±20 mg trospium BID) and the KarXT 100/20 BID group from KAR-003showed that C_(max) values and AUC_(0-6 hr) (KAR-003) or AUC_(0-tau)(KAR-001) values were greater in KAR-003 (Days 3 and 7) than thecorresponding exposures from KAR-001 (Days 3 and 9). The median T_(max)was observed at 2 hours in both studies and both days (Days 3 and 9 forKAR-001, and Days 3 and 7 for KAR-003). These data indicate that theKarXT formulation enhanced xanomeline exposures.

Trospium was absorbed into the systemic circulation following oraladministration of the KarXT formulation at all dosages. Peakconcentrations of trospium were observed at a median time of 1.0 houracross all treatment groups and study days.

Median t_(1/2) values for trospium were similar between treatment groupson Day 3, with values ranging between 4.1 and 4.8 hours. On Day 7,median t_(1/2) values were similar for the KarXT 100/20 BID (4.9 hours)and KarXT 125/40 BID (4.5 hours) treatments but were slightly longer forthe KarXT 150/40 BID group (7.1 hours).

GM trospium exposures increased slightly less than dose-proportionallyon Day 3 from 20 to 40 mg when administered with 150 mg xanomeline. Day3 GM trospium exposures (C_(max), AUC_(0-last), and AUC_(0-12 hr)) weregreater when the 20 mg BID dose of trospium was administered with 100 mgBID xanomeline compared to 150 mg BID xanomeline. Day 3 GM trospiumexposures were similar when the 40 mg trospium BID dose was given with125 mg xanomeline BID and 150 mg xanomeline BID.

Trospium did not accumulate in plasma from Day 3 to Day 7 followingadministration of KarXT 100/20 BID, KarXT 125/40 BID, and KarXT 150/40BID. Trospium accumulated in plasma from Day 1 to Day 7 for the KarXT100/20 BID group. Mean Day 7/Day 1 accumulation ratios were 348.7%(RAUC) and 379.9% (RC_(max)).

Comparing trospium GM exposures between KAR-001 and the KarXT 100/20 BIDgroup from KAR-003 showed that C_(max) and AUC_(0-12 hr) values fromKAR-003 were greater than the corresponding exposures from KAR-001 onboth days (Days 3 and 9 for KAR-001 and Days 3 and 7 for KAR-003). Themedian T_(max) for trospium was observed at 1.0 hour in both studies onboth days. These data indicate that the KarXT formulation enhancedtrospium exposures.

All cohorts of KAR-003 started with a 2-day lead-in period of KarXT50/20 BID for subjects randomized to KarXT. FIG. 42 presents the mean(±SD) xanomeline PK concentrations, and Table 22 summarizes xanomelinePK parameters on Day 1 for KarXT 50/20 BID treatment of all cohorts forthe PK Population. No sample collected before administering the firstdose of xanomeline on Day 1 displayed measurable concentrations ofxanomeline. Concentrations of xanomeline were quantifiable (>50 pg/mL)at all time points after administering the Day 1 morning dose through 12hours.

TABLE 22 Xanomeline PK Parameters on Day 1 for KarXT 50/20 BID (AllCohorts) Characteristic n Statistic C_(max) (pg/mL) 53  1972.3 (131.8)T_(max) (h) 53   2.0 (1.0, 8.0) t_(1/2) (h) 48   3.4 (2.0, 4.6)AUC_(0-last) (h*pg/mL) 53 10775.5 (102.2) AUC_(0-12hr) (h*pg/mL) 5210810.3 (103.5) AUC_(0-inf) (h*pg/mL) 48 12836.1 (97.7)

FIG. 43 presents the mean (±SD) xanomeline PK concentrations bytreatment on Day 3 for the PK population, and Table 23 summarizes theseparameters. Concentrations of xanomeline were quantifiable in samplesbefore administering the morning dose of study drug on Day 3 and at alltime points after administering the Day 3 morning dose through 12 hoursfor all cohorts, except for one subject who had a xanomeline plasmaconcentration <50.0 pg/mL at 12 hours post-dose. Inter-subjectvariability ranged from 23.7% to 58.2% (CV %) for T_(max), 79.8% to136.3% (geometric CV %) for C_(max), 21.6% to 26.3% (CV %) for t₁₁₂, and77.1% to 96.1% (geometric CV %) for AUC_(0-12 hr) across the fourtreatment groups. The median T_(max) for xanomeline on Day 3 was 2 hoursfor the KarXT 100/20 BID, KarXT 125/40 BID, KarXT 150/20 BID, and KarXT150/40 BID groups. Individual T_(max) values range from 1.0 to 6.0 hoursacross the four treatment groups. The t_(1/2) was estimated in 51 of 53subjects, in contrast to the previous study, KAR-001, where theelimination phase was not well characterized. The median t_(1/2) on Day3 for xanomeline was numerically similar across the four treatmentgroups. Median t_(1/2) ranged from 3.4 to 4.3 hours. Individual t_(1/2)values ranged from 2.4 to 8.6 hours across the four treatment groups.

TABLE 23 Xanomeline PK Parameters by Treatment on Day 3 Cohort 1 Cohort2 Cohort 3 Cohort 4 KarXT KarXT KarXT KarXT 100/20 BID 150/20 BID 150/40BID 125/40 BID Statistic n Statistic [2] n Statistic [2] n Statistic [2]n Statistic [2] C_(max) (pg/mL) 18 7368.4 (106.2) 5 7270.0 (79.8) 127866.7 (136.3) 18 8098.8 (99.1) T_(max) (h) 18 2.0 (1.0, 3.0) 5 2.0(2.0, 4.0) 12 2.0 (2.0, 6.0) 18 2.0 (1.0, 6.0) t_(1/2) (h) 17 3. 9 (3.0,5.8) 5 3.4 (2.4, 4.3) 12 3.6 (2.6, 6.1) 17 4.3 (3.1, 8.6) AUC_(0-last)18 42003.4 (86.9) 5 48031.1 (92.0) 12 39092.3 (96.1) 18 43450.2 (74.4)(h*pg/mL) AUC_(0-12hr) 17 40912.1 (88.8) 5 48132.2 (92.0) 12 39403.3(96.1) 17 43164.7 (77.1) (h*pg/mL) Dose-normalized 18 73.7 (106.2) 548.5 (79.8) 12 52.4 (136.3) 18 64.8 (99.1) C_(max) (pg/mL/mg)Dose-normalized 18 420.0 (86.9) 5 320.2 (92.0) 12 260.6 (96.1) 18 347.6(74.4) AUC_(0-last) (h*pg/mL/mg) Dose-normalized 17 409.1 (88.8) 5 320.9(92.0) 12 262.7 (96.1) 17 345.3 (77.1) AUC_(0-12hr) (h*pg/mL/mg)Geometric CV % = 100*(exp(SD²) − 1)^(0.5), where SD was the SD of thelog-transformed data. 1. Cohort 2 sentinel group (5 subjects randomizedto KarXT 150/20 BID and 1 subject randomized to placebo) wasdiscontinued after the Day 4 morning dose. 2. During the study, Cohort 3Group 3b (8 subjects randomized to KarXT 150/40 BID and 1 subjectrandomized to placebo) was discontinued after the Day 5 morning dose.

When KarXT was administered BID, as the xanomeline dose increased from100 mg (Cohort 1) to 150 mg (Cohort 2) without changing the trospiumdose (20 mg), the Day 3 dose-normalized GM exposures (dose-normalized GMC_(max) and dose-normalized GM AUC_(0-last) and AUC_(0-12 hr)) forxanomeline decreased. Similarly, as the xanomeline dose increased from125 mg (Cohort 4) to 150 mg (Cohort 3) without changing the trospiumdosage (40 mg), the Day 3 dose-normalized GM exposures for xanomelinedecreased slightly (i.e., xanomeline exposures were lower followingtreatment with KarXT 150/40 BID compared to treatment with KarXT 125/40BID). Comparing xanomeline exposures following administration of 150 mgxanomeline BID with either 20 or 40 mg trospium BID showed that the Day3 GM, C_(max), AUC_(0-last), and AUC_(0-12 hr) for xanomeline weresimilar.

FIG. 44 presents the mean (±SD) xanomeline PK concentrations bytreatment on Day 7 for the PK population, and Table 24 summarizes theseparameters. Concentrations of xanomeline were quantifiable in samplescollected before administering the morning dose of the study drug on Day7 and at all time points after the Day 7 morning dose through 12 hoursfor the KarXT 100/20 BID, KarXT 125/40 BID, and KarXT 150/40 BID groups.Inter-subject variability ranged from 38.3% to 47.9% (CV %) for T_(max),81.4% to 106.8% (geometric CV %) for C_(max), 15.4% to 42.1% (CV %) fort_(1/2), and 45.2% to 71.2% (geometric CV %) for AUC_(0-12 hr) acrossthe KarXT 100/20 BID, KarXT 150/40 BID, and KarXT 125/40 BID groups. Themedian T_(max) for xanomeline on Day 7 was 2.0 hours for the KarXT100/20 BID, KarXT 125/40 BID, and KarXT 150/40 BID groups. IndividualT_(max) values ranged from 0.0 to 6.0 hours across the KarXT 100/20 BID,KarXT 150/40 BID, and KarXT 125/40 BID groups. The median t_(1/2) forxanomeline on Day 7 was numerically similar for the KarXT 100/20 BID,KarXT 125/40 BID, and KarXT 150/40 BID groups. Median t_(1/2) forxanomeline ranged from 4.6 to 5.8 hours. Individual t_(1/2) valuesranged from 3.6 to 14.0 hours across the KarXT 100/20 BID, KarXT 150/40BID, and KarXT 125/40 BID groups.

TABLE 24 Xanomeline PK Parameters by Treatment on Day 7 Cohort 1 Cohort2 Cohort 3 Cohort 4 KarXT KarXT KarXT KarXT 100/20 BID 150/20 BID 150/40BID 125/40 BID Statistic n Statistic [1] n Statistic [1] n Statistic [1]n Statistic [1] C_(max) (pg/mL) 16 8373.6 (94.3) N/A N/A 4 18191.3(81.4) 18 8112.7 (106.8) T_(max) (h) 16 2.0 (0.0, 3.0) N/A N/A 4 2.0(1.0, 3.0) 18 2.0 (1.0, 6.0) t_(1/2) (h) 15 5.4 (3.6, 9.9) N/A N/A 4 4.6(3.9, 5.6) 17 5.7 (4.0, 14.0) AUC_(0-last) 16 53810.8 (89.8) N/A N/A 486347.8 (45.3) 18 52727.0 (76.7) (h*pg/mL) AUC_(0-12hr) 15 48138.3(71.2) N/A N/A 4 86540.9 (45.2) 17 59945.1 (45.9) (h*pg/mL)Dose-normalized 16 83.7 (94.3) N/A N/A 4 121.3 (81.4) 18 64.9 (106.8)C_(max) (pg/mL/mg) Dose-normalized 16 538.1 (89.8) N/A N/A 4 575.7(45.3) 18 421.8 (76.7) AUC_(0-last) (h*pg/mL/mg) Dose-normalized 15481.4 (71.2) N/A N/A 4 576.9 (45.2) 17 479.6 (45.9) AUC_(0-12hr)(h*pg/mL/mg) Geometric CV % = 100*(exp(SD²) − 1)^(0.5), where SD was theSD of the log-transformed data. 1. Cohort 2 sentinel group (5 subjectsrandomized to KarXT 150/20 BID and 1 subject randomized to placebo) wasdiscontinued after the Day 4 morning dose. 2. During the study, Cohort 3Group 3b (8 subjects randomized to KarXT 150/40 BID and 1 subjectrandomized to placebo) was discontinued after the Day 5 morning dose.

When KarXT was administered BID, as the xanomeline dose increased from125 mg (Cohort 4) to 150 mg (Cohort 3) without changing the trospiumdosage (40 mg), the Day 7 dose-normalized GM exposures (dose-normalizedGM C_(max), AUC_(0-last), and AUC_(0-12 hr)) for xanomeline increased.

Table 25 summarizes xanomeline PK accumulation ratios (Day 7/Day 3) bytreatment for the PK population. Based upon mean accumulation ratios ofxanomeline following treatment with KarXT 100/20 BID (Cohort 1) andKarXT 125/40 BID (Cohort 4), minimal to no xanomeline accumulated inplasma from Day 3 to Day 7. Mean accumulation ratios for the KarXT100/20 BID group were 133.4% for RAUC and 130.5% for RC_(max), and forthe KarXT 125/40 BID group were 143.9% for RAUC and 151.0% for RC_(max).Only one subject in the KarXT 100/20 BID group showed lower exposures onDay 7 compared to Day 3. In contrast, xanomeline accumulated moderatelyin three of the four subjects in the KarXT 150/40 BID group whocompleted the study. The other subject in the KarXT 150/40 BID groupshowed similar exposures on Days 3 and 7. The mean accumulation ratiosfor the KarXT 150/40 BID group were 366.2% (RAUC) and 445.4% (RC_(max)).

TABLE 25 Xanomeline PK Accumulation Ratios (Day 7/Day 3) by TreatmentCohort 1 Cohort 2 Cohort 3 Cohort 4 KarXT KarXT 150/20 KarXT KarXT100/20 BID BID [1] 150/40 BID [2] 125/40 BID Mean Mean Mean MeanStatistic n (SD) n (SD) n (SD) n (SD) RAUC (%) 14 133.4 (45.1) N/A N/A(N/A) 4 366.2 (321.3) 16 143.9 (80.9) RC_(max) (%) 16 130.5 (55.1) N/AN/A (N/A) 4 445.4 (537.0) 18 151.0 (122.7) RAUC = 100*Day 7AUC_(0-12hr)/Day 3 AUC_(0-12hr). RC_(max) = 100*Day 7 C_(max)/Day 3C_(max). 1. Cohort 2 sentinel group (5 subjects randomized to KarXT150/20 BID and 1 subject randomized to placebo) was discontinued afterthe Day 4 morning dose. 2. During the study, Cohort 3 Group 3b (8subjects randomized to KarXT 150/40 BID and 1 subject randomized toplacebo) was discontinued after the Day 5 morning dose.

FIG. 45 compares the mean (±SD) xanomeline PK concentration-timeprofiles by treatment and visit (Day) for the PK population. FIG. 46presents mean (±SD) xanomeline PK trough concentrations by treatment forthe PK population. Attaining a steady state was not assessed.

Comparing xanomeline GM exposures between KAR-001 (75 mg xanomelineTID±20 mg trospium BID) (Table 23) and the KarXT 100/20 BID group fromKAR-003 (Table 21) showed that C_(max) values and AUC_(0-6 hr) (KAR-003)or AUC_(0-tau) (AUC from time 0 to 6 hours) values (KAR-001) values onDay 3 for the KarXT 100/20 BID group (KAR-003) were about 2.3 to2.6-fold greater than corresponding exposures from KAR-001 on Day 3.

Comparing Day 7 GM exposures for xanomeline for the KarXT 100/20 BIDgroup from KAR-003 (Table 22) with Day 9 exposures from the xanomelinealone and xanomeline+trospium arms from KAR-001 (Table 23) showed thatvalues on Day 7 for the KarXT 100/20 BID group (KAR-003) were about 1.4to 1.8-fold greater than corresponding exposures from KAR-001 on Day 9.The median T_(max) was 2.0 hours on Day 3 and Day 7 for KAR-003 (Table22) and Day 3 and Day 9 for KAR-001 (Table 23). These data indicate thatthe KAR-003 formulation provided sufficient exposure and PK properties.

Table 26 summarizes a subset of KAR-003 xanomeline PK parameters for theKarXT 100/20 BID group on Day 3 and Day 7 for the PK Population. Table27 presents a summary of a subset of KAR-001 xanomeline PK parametersfor the treatments of KAR-001 on Day 3 and Day 9 for the PK Population.

TABLE 26 Subset of Xanomeline PK Parameters KarXT 100/20 BID on Days 3and 7 Cohort 1 - KarXT Cohort 1 - KarXT KAR-003 100/20 BID 100/20 BID PKParameter Day 3 Day 7 Statistic n Statistic [1] n Statistic [1] C_(max)(pg/mL) 18  7368.4 (106.2) 16  8373.6 (94.3) T_(max) (h) 18   2.0 (1.0,3.0) 16   2.0 (0.0, 3.0) AUC_(0-6hr) (h*pg/mL) 18 28564.2 (88.2) 1635129.1 (85.2)

TABLE 27 Subset Xanomeline PK Parameters for KAR-001 on Days 3 and 9KAR-001 PK Xanomeline Alone [1] Xanomeline + Trospium [2] Parameter Day3 Day 9 Day 3 Day 9 Statistic n Statistic [3] n Statistic [3] nStatistic [3] n Statistic [3] C_(max) (pg/mL) 32 2951.1 (107.7) 314572.6 (123.5) 34 3043.0 (84.5) 32 4698.5 (99.5) T_(max) (h) 32 2.0(2.0, 5.9) 31 2.0 (0.0, 5.9) 34 2.0 (1.0, 5.9) 32 2.0 (1.0, 4.0)AUC_(0-tau) 11 12585.1 (132.4) 21 24808.6 (85.4) 17 11638.8 (71.3) 2220347.9 (107.3) (h*pg/mL) Geometric CV % = 100*(exp(SD²) −1)^(0.5),where SD was the SD of the log-transformed data. In KAR-001,xanomeline dosing started on Day 3. Hence Day 3 is the first day ofxanomeline dosing and Day 9 is the seventh day of xanomeline dosing. 1.In KAR-001, the xanomeline-alone treatment arm received 2 placebocapsules TID during the 2-day lead-in phase, then xanomeline 75 mg TID(TDD 225 mg) and placebo on Days 3 through 9. 2. In KAR-001, thexanomeline plus trospium arm received trospium 20 mg BID (TDD 40 mg) andplacebo BID; and 2 placebo capsules QD during the 2-day lead-in phase;then xanomeline 75 mg TID and trospium 20 mg BID (TDD 40 mg) and placeboQD on Days 3 through 9. 3. Statistics for parameters presented asgeometric mean (geometric CV %), except for T_(max), which is presentedas the median with minimum and maximum values.

FIG. 47 presents mean (±SD) trospium PK concentrations on Day 1 for theKarXT 50/20 BID treatment (all cohorts) for the PK population, and Table28 summarizes these parameters. No samples collected beforeadministering the first dose of trospium on Day 1 displayed measurableconcentrations of trospium. Concentrations of trospium were quantifiable(>20 pg/mL) at all time points after administration of the Day 1 morningdose through 12 hours.

TABLE 28 Trospium PK Parameters on Day 1 for KarXT 50/20 BID (AllCohorts) Statistic n Statistic [1] C_(max) (pg/mL) 53  1824.7 (98.7)T_(max) (h) 53   1.0 (1.0, 10.0) t_(1/2) (h) 26   4.5 (3.2, 5.1)AUC_(0-last) (h*pg/mL) 53 10286.5 (86.3) AUC_(0-12hr) (h*pg/mL) 4910623.7 (78.5) AUC_(0-inf) (h*pg/mL) 26 16526.6 (70.6) Geometric CV % =100*(exp(SD²) − 1)^(0.5), where SD was the SD of the log-transformeddata. 1. Statistics for parameters are presented as geometric mean(geometric CV %), except for t_(1/2) and T_(max), which are presented asmedians with minimum and maximum values.

FIG. 48 presents mean (±SD) trospium PK concentrations by treatment onDay 3 for the PK population, and Table 29 summarizes these parameters.Concentrations of trospium were quantifiable in samples collected beforeadministering the morning dose of the study drug on Day 3 and at alltime points after administering the Day 3 morning dose through 12 hoursfor all treatment groups (except for one subject who had a trospiumplasma concentration <20.0 pg/mL at 12 hours post-dose. Inter-subjectvariability ranged from 0.0% to 83.0% (CV %) for T_(max), 54.8% to 80.7%(geometric CV %) for C_(max), 9.1% to 34.0% (CV %) for t_(1/2), and59.0% to 67.6% (geometric CV %) for AUC_(0-12 hr) across the fourtreatment groups.

TABLE 29 Trospium PK Parameters by Treatment on Day 3 Cohort 2 Cohort 3Cohort 4 Cohort 1 KarXT KarXT KarXT KarXT 150/20 150/40 125/40 100/20BID BID [1] BID [2] BID Statistic [3] n Statistic n Statistic nStatistic n Statistic C_(max) (pg/mL) 18 5705.6 (80.7) 5 3109.0 (54.8)12 9838.7 (67.3) 18 8496.4 (74.9) T_(max) (h) 18 1.0 (1.0, 3.0) 5 1.0(1.0, 1.0) 12 1.0 (1.0, 2.0) 18 1.0 (1.0, 6.0) t_(1/2) (h) 18 4.8 (3.3,7.6) 5 4.6 (4.3, 5.3) 12 4.1 (3.0, 8.0) 18 4.2 (2.8, 9.0) AUC^(0-last)18 29175.4 (59.0) 5 17560.8 (64.8) 12 43581.1 (64.4) 18 46214.2 (67.5)(h*pg/mL) AUC_(0-12hr) 18 29253.9 (59.0) 5 17612.9 (64.8) 12 44072.6(64.3) 18 46333.3 (67.6) (h*pg/mL) Dose-normalized 18 285.3 (80.7) 5155.5 (54.8) 12 246.0 (67.3) 18 212.4 (74.9) C_(max) (pg/mL/mg)Dose-normalized 18 1458.8 (59.0) 5 878.0 (64.8) 12 1089.5 (64.4) 181155.4 (67.5) AUC_(0-last) (h*pg/mL/mg) Dose-normalized 18 1462.7 (59.0)5 880.6 (64.8) 12 1101.8 (64.3) 18 1158.3 (67.6) AUC_(0-12hr)(h*pg/mL/mg) Geometric CV % = 100*(exp(SD²) − 1)^(0.5), where SD was theSD of the log-transformed data. 1. Cohort 2 sentinel group (5 subjectsrandomized to KarXT 150/20 BID and 1 subject randomized to placebo) wasdiscontinued after the Day 4 morning dose. 2. During the study, Cohort 3Group 3b (8 subjects randomized to KarXT 150/40 BID and 1 subjectrandomized to placebo) was discontinued after the Day 5 morning dose. 3.Statistics for parameters presented as geometric mean (geometric CV %),except for t_(1/2) and T_(max) which are presented as medians withminimum and maximum values.

The median T_(max) for trospium on Day 3 was 1.0 hour for the KarXT100/20 BID, KarXT 125/40 BID, KarXT 150/20 BID, and KarXT 150/40 BIDgroups. Individual T_(max) values ranged from 1.0 to 6.0 hours acrossthe 4 treatment groups. The median t_(1/2) for trospium on Day 3 wasnumerically similar across the 4 treatment groups; median t_(1/2) rangedfrom 4.1 to 4.8 hours. Individual t_(1/2) values ranged from 2.8 to 9.0hours across the 4 treatment groups.

When KarXT was administered BID, as the trospium dose increased from 20mg (Cohort 2) to 40 mg (Cohort 3) without changing xanomeline dose (150mg), the Day 3 dose-normalized GM exposures for trospium increased.Comparing Day 3 trospium exposures following administration of 20 mgtrospium BID with either 100 mg (Cohort 1) or 150 mg (Cohort 2)xanomeline BID showed that GM C_(max), AUC_(0-last), and AUC_(0-12 hr)for trospium were greater when the 20 mg BID dose of trospium wasadministered with 100 mg xanomeline BID compared to 150 mg xanomelineBID.

Similarly, comparing trospium exposures following administration of 40mg trospium BID with either 125 mg (Cohort 4) or 150 mg (Cohort 3)xanomeline BID showed that the GM C_(max), AUC_(0-last), andAUC_(0-12 h) for trospium were generally similar when trospium wasadministered with 125 and 150 mg xanomeline BID on Day 3.

FIG. 49 presents mean (±SD) trospium PK concentrations by treatment onDay 7 for the PK population, and Table 30 summarizes the parameters.Concentrations of trospium were quantifiable in samples collected beforeadministering the morning dose of the study drug on Day 7 and at alltime points after the Day 7 morning dose through 12 hours for the KarXT100/20 BID, KarXT 125/40 BID, and KarXT 150/40 BID groups. Inter-subjectvariability ranged from 0.0% to 86.3% (CV %) for T_(max), 51.2% to 93.8%(geometric CV %) for C_(max), 23.0% to 44.5% (CV %) for t_(1/2), and59.4% to 76.7% (geometric CV %) for AUC_(0-12 hr) across the KarXT100/20 BID, KarXT 150/40 BID, and KarXT 125/40 BID groups.

TABLE 30 Trospium PK Parameters by Treatment on Day 7 Cohort 1 Cohort 2Cohort 3 Cohort 4 KarXT KarXT KarXT KarXT 100/20 150/20 150/40 125/40BID BID [1] BID [2] BID Statistic [3] n Statistic n Statistic nStatistic n Statistic C_(max) (pg/mL) 16 7494.9 (88.3) N/A N/A (N/A) 49588.0 (51.2) 18 7213.8 (93.8) T_(max) (h) 16 1.0 (0.0, 1.0) N/A N/A 41.0 (1.0, 1.0) 18 1.0 (0.0, 6.0) t_(1/2) (h) 16 4.9 (3.1, 7.1) N/A N/A 47.1 (4.4, 8.2) 18 4.5 (3.7, 11.9) AUC_(0-last) 16 40377.8 (69.3) N/A N/A(N/A) 4 41865.2 (59.4) 18 44998.6 (76.7) (h*pg/mL) AUC_(0-12hr) 1640488.0 (69.3) N/A N/A (N/A) 4 41997.6 (59.4) 18 45137.6 (76.7)(h*pg/mL) Dose-normalized 16 374.7 (88.3) N/A N/A (N/A) 4 239.7 (51.2)18 180.3 (93.8) C_(max) (pg/mL/mg) Dose-normalized 16 2018.9 (69.3) N/AN/A (N/A) 4 1046.6 (59.4) 18 1125.0 (76.7) AUC_(0-last) (h*pg/mL/mg)Dose-normalized 16 2024.4 (69.3) N/A N/A (N/A) 4 1049.9 (59.4) 18 1128.4(76.7) AUC_(0-12hr) (h*pg/mL/mg) Geometric CV % = 100*(exp(SD²) −1)^(0.5), where SD was the SD of the log-transformed data. 1. Cohort 2sentinel group (5 subjects randomized to KarXT 150/20 BID and 1 subjectrandomized to placebo) was discontinued after the Day 4 morning dose. 2.During the study, Cohort 3 Group 3b (8 subjects randomized to KarXT150/40 BID and 1 subject randomized to placebo) was discontinued afterthe Day 5 morning dose. 3. Statistics for parameters presented asgeometric mean (geometric CV %), except for t_(1/2) and T_(max) whichare presented as medians with minimum and maximum values.

The median T_(max) for trospium on Day 7 was 1.0 hour for the KarXT100/20 BID, KarXT 125/40 BID, and KarXT 150/40 BID treatments.Individual T_(max) values ranged from 0.0 to 6.0 hours across the KarXT100/20 BID, KarXT 150/40 BID, and KarXT 125/40 BID groups.

The median t_(1/2) for trospium on Day 7 was similar for the KarXT100/20 BID (4.9 hours) and KarXT 125/40 BID (4.5 hours) groups. Themedian t_(1/2) was 7.1 hours for the KarXT 150/40 BID group. Individualt_(1/2) values ranged from 3.1 to 11.9 hours across the KarXT 100/20BID, KarXT 150/40 BID, and KarXT 125/40 BID groups.

As observed on Day 3, comparing Day 7 trospium exposures followingadministration of 40 mg trospium BID with either 125 mg (Cohort 4) or150 mg (Cohort 3) xanomeline BID showed that the GM C_(max),AUC_(0-last), and AUC_(0-12 hr) for trospium were similar when trospiumwas administered with 125 and 150 mg xanomeline BID.

Table 31 summarizes trospium PK accumulation ratios (Day 7/Day 3; Day7/Day 1) by treatment for the PK Population. Based upon mean trospium PKaccumulation ratios, trospium accumulated minimally in the plasma fromDay 3 to Day 7 following administration of KarXT 100/20 BID (Cohort 1)and had little to no accumulation following administration of KarXT125/40 BID (Cohort 4) and KarXT 150/40 BID (Cohort 3). Two subjectsshowed lower exposures on Day 7 compared to Day 3 in the KarXT 100/20BID group.

Accumulation ratios from Day 3 to Day 7 varied widely between subjectsin the KarXT 125/40 BID and KarXT 150/20 BID groups. Mean accumulationratios ranged from 108.6% to 141.4% for RAUC and from 111.0% to 135.8%for RC_(max). Trospium accumulated moderately in the plasma from Day 1to Day 7 for the KarXT 100/20 BID group. All but one subject showedhigher trospium exposures on Day 7 compared to Day 1. Mean accumulationratios were 348.7% for RAUC and 379.9% for RC_(max). The possible effectof the increase in xanomeline dose (from 50 mg BID to 100 mg BIDbeginning on Day 3) on the PK and bioavailability of trospium cannot beruled out as contributing to the increased exposures from Day 1 to Day7.

TABLE 31 Trospium PK Accumulation Ratios (Day 7/Day 3; Day7/Day 1) byTreatment Cohort 1 Cohort 2 Cohort 3 Cohort 4 KarXT KarXT KarXT KarXT100/20 150/20 150/40 125/40 BID BID [1] BID [2] BID Statistic n Mean(SD) n Mean (SD) n Mean (SD) n Mean (SD) Day 7/Day 3 RAUC (%) 16 141.4(56.6) N/A N/A (N/A) 4 108.6 (39.0) 18 125.0 (84.4) RC_(max) (%) 16135.8 (70.5) N/A N/A (N/A) 4 111.0 (67.8) 18 119.9 (91.0) Day 7/Day 1RAUC (%) 15 348.7 (242.9) N/A N/A (N/A) N/A N/A (N/A) N/A N/A (N/A)RC_(max) (%) 16 379.89 (266.0) N/A N/A (N/A) N/A N/A (N/A) N/A N/A(N/A) 1. Pharmacokinetic accumulation ratios of Day7/Day3: RAUC =100*Day 7 AUC_(0-12hr)/Day 3 AUC_(0-12hr). RC_(max) = 100*Day 7C_(max)/Day 3 C_(max). 2. Pharmacokinetic accumulation ratios of Day7/Day 1: RAUC = 100*Day 7 AUC_(0-12hr)/Day 1 AUC_(0-12hr). RC_(max) =100*Day 7 C_(max)/Day 1 C_(max). 3. Cohort 2 sentinel group (5 subjectsrandomized to KarXT 150/20 BID and 1 subject randomized to placebo) wasdiscontinued after the Day 4 morning dose. 4. During the study, Cohort 3Group 3b (8 subjects randomized to KarXT 150/40 BID and 1 subjectrandomized to placebo) was discontinued after the Day 5 morning dose.

FIG. 50 compares mean (±SD) trospium PK concentration-time profiles bytreatment and visit (Day) for the PK Population. FIG. 51 presents mean(±SD) trospium PK trough concentrations by treatment and visit (Day) forthe PK Population. Attaining steady state was not assessed.

Example 7—Trospium Pharmacokinetics of KAR-003 Compared to KAR-001

Comparing GM exposures for trospium from Day 1 of KAR-001 (first dose oftrospium alone with no prior treatment) (Table 33) and Day 1 of KAR-003(first dose of xanomeline+trospium with no prior treatment) (Table 32)shows that the trospium exposures from KAR-003 are about 2.1- to2.5-fold higher than those obtained from KAR-001. Although thecomparison of Day 3 GM exposures between studies is not really ahead-to-head comparison (xanomeline dosing did not start until Day 3 inthe KAR-003 study), the number of doses and the daily dose of trospiumadministered to subjects is the same. The Day 3 GM trospium exposuresfrom KAR-003 (Table 32) are also ˜2.4- to 3.3-fold higher than thoseobtained from KAR-001 (Table 33). Comparing Day 7 GM exposures fortrospium for the KarXT 100/20 BID cohort (Cohort 1) from KAR-003 (Table32) with Day 9 exposures from the xanomeline+trospium arm from KAR-001(Table 33) indicates that exposures were once again higher (byapproximately 3.5- to 4.3-fold) than those obtained from KAR-001.

The median T_(max) for trospium was 1.0 hour on Day 3 and Day 7 for theKarXT 100/20 BID group for KAR-003 and on Day 3 and Day 9 for thexanomeline+trospium arm for KAR-001. Median T_(max) for trospium waslower (1.0 hour) on Day 1 for the KarXT 50/20 BID group (KAR-003)compared to the median T_(max) for trospium (3.0 hours on Day 1 for thetrospium alone arm (KAR-001).

Table 32 summarizes a subset of KAR-003 trospium PK parameters for theKarXT 50/20 BID treatment (all cohorts) on Day 1 and for the KarXT100/20 BID treatment on Day 3 and Day 7 for the PK Population. Table 33summarizes a subset of KAR-001 trospium PK parameters for thetrospium-alone treatment on Day 1 and the xanomeline+trospium treatmenton Day 3 and Day 9 for the PK Population.

TABLE 32 Subset of KAR-003 Trospium PK Parameters for KarXT 50/20 BID(All Cohorts) on Day 1 and KarXT 100/20 BID on Days 3 and 7 KAR 50/20BID Cohort 1-KAR 100/20 BID KAR-003 PK Day 1 Day 3 Day 7 Parameter nStatistic [1] n Statistic [1] n Statistic [1] C_(max) (pg/mL) 53 1824.7(98.7) 18 5705.6 (80.7) 16 7494.9 (88.3) T_(max) (h) 53 1.0 (1.0, 10.0)18 1.0 (1.0, 3.0) 16 1.0 (0.0, 1.0) AUC_(0-12hr) (h*pg/mL) 49 10623.7(78.5) 18 29253.9 (59.0) 16 40488.0 (69.3) AUC_(0-inf) (h*pg/mL) 2616526.6 (70.6) N/A N/A N/A N/A 1. Statistics for parameters arepresented as geometric mean (geometric CV %), except for T_(max) whichis presented as the median with minimum and maximum values.

TABLE 33 Subset of Trospium PK Parameters for KAR-001 on Days 1, 3, and9 Trospium Alone [1] Xanomeline + Trospium [1] KAR-001 PK Day 1 Day 3Day 9 Parameter n Statistic [2] n Statistic [2] n Statistic [2] C_(max)(pg/mL) 33 721.9 (78.2) 34 1711.6 (89.8) 33 1733.6 (124.1) T_(max) (h)33 3.0 (1.0, 5.9) 34 1.0 (1.0, 5.9) 33 1.0 (0.0, 4.0) AUC_(0-tau)(h*pg/mL) 26 5028.6 (65.9) 23 12176.3 (61.6) 30 11395.2 (105.9)AUC_(0-inf) (h*pg/mL) 26 7787.3 (55.4) 23 18149.4 (62.0) 30 17519.4(93.2) Geometric CV % = 100*(exp(SD²) − 1)^(0.5), where SD is thestandard deviation of the log- transformed data. In KAR-001, xanomelinedosing started on Day 3. Hence Day 3 is the first day of xanomelinedosing and Day 9 is the seventh day of xanomeline dosing. 1. In KAR-001,the xanomeline + trospium arm received 20 mg trospium BID (TDD 40 mg)and placebo BID; and 2 placebo capsules QD during the 2-day lead-inphase; then 75 mg xanomeline TID and 20 mg trospium BID (TDD 40 mg) andplacebo QD on Days 3 through 9. 2. Statistics for parameters arepresented as geometric mean (geometric CV %), except for T_(max) whichis presented as the median with minimum and maximum values.

Table 34 lists the incidence of cholinergic TEAEs by system organ class(SOC) and preferred term for the Safety Population in the KAR-001 study.The overall subject incidence of cholinergic TEAEs was similar betweenthe xanomeline+trospium arm (12 [34.3%] subjects) in KAR-001, the KarXT100/20 BID group (7 [38.9%] subjects), and the KarXT 125/40 BID group (6[33.3%] subjects).

TABLE 34 KAR-001 Incidence of Cholinergic Treatment-Emergent AdverseEvents by System Organ Class and Preferred Term - Safety PopulationXanomeline Xanomeline + Alone [1] Trospium [2] Total System Organ Class(n = 34) (n = 35) (n = 69) Preferred Term n (%) # n (%) # n (%) #Subjects with any TEAEs 21 (61.8) 64 12 (34.3) 33 33 (47.8) 97Gastrointestinal disorders 18 (52.9) 40 12 (34.3) 25 30 (43.5) 65Salivary hypersecretion 12 (35.3) 16  9 (25.7) 11 21 (30.4) 27 Nausea  8(23.5) 11  6 (17.1) 8 14 (20.3) 19 Diarrhea  7 (20.6) 8  2 (5.7) 4  9(13.0) 12 Vomiting  5 (14.7) 5  2 (5.7) 2  7 (10.1) 7 Skin andsubcutaneous 16 (47.1) 24  7 (20.0) 8 23 (33.3) 32 tissue disordersHyperhidrosis 16 (47.1) 24  7 (20.0) 8 23 (33.3) 32 The percentage wascalculated from the number of subjects in the column header as thedenominator. # was the number of individual occurrences of the TEAE. TheTEAEs were defined as adverse events that happened for the first timeafter dosing of study drug or existed before but worsened in severity orrelationship to study drug after dosing. For noncholinergic adverseevents, the first dose of any study drug (Day 1) was used, and forcholinergic adverse events, the first dose of xanomeline (Day 3) wasused. Cholinergic adverse events had the additional specification thatthe start of the adverse event must have been within 24 hours(inclusive) of the last dose to be treatment-emergent. At each level ofsummation (total, system organ class term, preferred term), subjects whoreported more than one adverse event were counted only once. During thestudy, a subject could have contributed to more than one preferred term.In KAR-001, xanomeline dosing started on Day 3. Hence Day 3 was thefirst day of xanomeline dosing and Day 9 was the seventh day ofxanomeline dosing. 1. In KAR-001, the xanomeline-alone treatment armreceived two placebo capsules TID during the 2-day lead-in phase, thenxanomeline 75 mg TID (TDD 225 mg) and placebo on Days 3 through 9. 2. InKAR-001, the xanomeline + trospium arm received trospium 20 mg BID (TDD40 mg) and placebo BID; and two placebo capsules QD during the 2-daylead-in phase; then xanomeline 75 mg TID and trospium 20 mg BID (TDD 40mg) and placebo QD on Days 3 through 9.

Subject incidence of salivary hypersecretion, hyperhidrosis, anddiarrhea was higher in the xanomeline+trospium arm in KAR-001 comparedto the KarXT 100/20 BID and KarXT 125/40 BID groups. Salivaryhypersecretion occurred in 25.7% of subjects in the xanomeline+trospiumarm in KAR-001, 5.6% of subjects in the KarXT 100/20 BID group, and nosubjects in the KarXT 125/40 BID group. Hyperhidrosis occurred in 20.0%of subjects in the xanomeline+trospium arm in KAR-001, 5.6% of subjectsin the KarXT 100/20 BID group, and 11.1% of subjects in the KarXT 125/40BID group. Diarrhea occurred in 5.7% of subjects in thexanomeline+trospium arm in KAR-001, and no subjects in the KarXT 100/20BID group or the KarXT 125/40 BID group.

The xanomeline+trospium arm in KAR-001 showed no other apparent trendscompared to the KarXT 100/20 BID and KarXT 125/40 BID groups for nauseaand vomiting. Nausea occurred in 17.1% of subjects in thexanomeline+trospium arm in KAR-001 and 22.2% of subjects in each KarXT100/20 BID and KarXT 125/40 BID groups. Vomiting occurred in 5.7% ofsubjects in the xanomeline+trospium arm in KAR-001, 27.8% of subjects inthe KarXT 100/20 BID group, and 5.6% of subjects in the KarXT 125/40 BIDgroup.

Xanomeline and trospium were absorbed into the systemic circulationfollowing oral administration of the KAR-003 formulation at all dosages.The PK results suggest that neither xanomeline nor trospium meaningfullyimpacted the PK behavior of the other drug. The KAR-003 formulationprovided enhanced xanomeline and trospium blood levels compared toKAR-001, where both compounds were dosed apart.

No new safety signals were reported with the KarXT formulation. AllTEAEs were mild or moderate in severity with no SAEs or deaths. Subjectincidence of salivary hypersecretion, hyperhidrosis, and diarrhea washigher in the xanomeline+trospium arm in KAR-001 compared to the KarXT100/20 BID and KarXT 125/40 BID groups in KAR-003.

The foregoing description is given for clearness of understanding only,and no unnecessary limitations should be understood therefrom, asmodifications within the scope of the disclosure may be apparent tothose having ordinary skill in the art. Throughout the specification,where compositions are described as including components or materials,it is contemplated that the compositions can also consist essentiallyof, or consist of, any combination of the recited components ormaterials, unless described otherwise. Likewise, where methods aredescribed as including steps, it is contemplated that the methods canalso consist essentially of, or consist of, any combination of therecited steps, unless described otherwise. The disclosure illustrativelydisclosed herein suitably may be practiced in the absence of any elementor step which is not specifically disclosed herein.

The practice of a method disclosed herein, and individual steps thereof,can be performed manually and/or with the aid of or automation providedby electronic equipment. Although processes have been described withreference to embodiments, a person of ordinary skill in the art willreadily appreciate that other ways of performing the acts associatedwith the methods may be used. For example, the order of various of thesteps may be changed without departing from the scope or spirit of themethod unless described otherwise. In addition, some of the individualsteps can be combined, omitted, or further subdivided into additionalsteps.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables containedwithin the generic chemical formulae described herein are specificallyembraced by the present invention just as if each and every combinationwas individually explicitly recited, to the extent that suchcombinations embrace stable compounds (i.e., compounds that can beisolated, characterized and tested for biological activity). Inaddition, all subcombinations of the chemical groups listed in theembodiments describing such variables, as well as all subcombinations ofuses and medical indications described herein, are also specificallyembraced by the present invention just as if each and everysubcombination of chemical groups and subcombination of uses and medicalindications was individually and explicitly recited herein.

All patents, publications, and references cited herein are hereby fullyincorporated by reference. In case of conflict between the presentdisclosure and incorporated patents, publications, and references, thepresent disclosure should control.

1. (canceled)
 2. A method of treating a disorder ameliorated byactivating muscarinic receptors in a patient in need thereof, the methodcomprising administering between 100 mg and 125 mg xanomeline and/or asalt thereof and between 20 mg and 30 mg trospium salt to the patienttwice daily.
 3. The method of claim 2, wherein the disorder is chosenfrom schizophrenia, Alzheimer's disease, Parkinson's disease,depression, movement disorders, pain, drug addiction, tauopathy, andsynucleinopathy.
 4. The method of claim 2, wherein the disorder isschizophrenia.
 5. The method of claim 2, wherein the administration isoral.
 6. The method of claim 2, wherein the patient is treated for atleast 7 days.
 7. The method of claim 2, wherein the xanomeline and/or asalt thereof is xanomeline tartrate.
 8. The method of claim 2, whereinthe trospium salt is trospium chloride.
 9. The method of claim 2,wherein the xanomeline and/or a salt thereof is xanomeline tartrate andthe trospium salt is trospium chloride.
 10. The method of claim 2,wherein the xanomeline and/or a salt thereof and trospium salt areadministered as a pharmaceutical composition comprising a plurality ofxanomeline beads having a core comprising the xanomeline or a saltthereof and optionally a coating, and a plurality of trospium beadshaving a core comprising the trospium salt and optionally a coating. 11.The method of claim 10, wherein the pharmaceutical composition is acapsule containing the plurality of xanomeline beads and the pluralityof trospium beads.
 12. A method of treating schizophrenia in a patientin need thereof, the method comprising orally administering between 100mg and 125 mg xanomeline tartrate and between 20 mg and 30 mg trospiumchloride to the patient twice daily.
 13. The method of claim 12, whereinthe patient is treated for at least 7 days.
 14. The method of claim 12,wherein the xanomeline and/or a salt thereof and trospium salt areadministered as a pharmaceutical composition comprising a plurality ofxanomeline beads having a core comprising the xanomeline or a saltthereof and optionally a coating, and a plurality of trospium beadshaving a core comprising the trospium salt and optionally a coating.